Original Research
Association of History of Surgery for Endometriosis With Severity of Deeply Infiltrating Endometriosis Jeanne Sibiude, MD, Pietro Santulli, MD, PhD, Louis Marcellin, Bertrand Dousset, MD, and Charles Chapron, MD OBJECTIVE: To assess whether a history of surgery for endometriosis could be considered as a marker for disease severity. METHODS: This cross-sectional study included 780 women with histologically proven endometriosis who underwent surgery. We compared 309 patients with a history of surgery for endometriosis (study group) with 471 patients who did not receive prior surgical intervention (control group). Multivariate logistic regression was performed to assess the risk of deeply infiltrating endometriosis (defined by invasion of the muscularis by endometriotic tissue). RESULTS: Patients with a history of surgery displayed an increased prevalence of deeply infiltrating endometriosis (242 patients [78.3%] compared with 210 patients [44.6%], respectively; P,.001). Moreover, the study group showed significantly higher stage, mean total (P,.001), and mean adhesions (P,.001) scores based on the American Society for Reproductive Medicine classification system. Furthermore, history of previous surgery remained independently associated with the presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped together) in multivariate From the Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Inserm, Unité de Recherche U1016, Université Paris Descartes, Faculté de Médecine, EA 1833, ERTi, AP-HP, CHU cochin, and Université Paris Descartes, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, Department of Digestive and Endocrine Surgery, Paris, France. The authors thank surgeons from the department for their expert assistance with data collection and Nathalie Girma for unabatedly managing the database. Corresponding author: Charles Chapron, MD, Service de Gynécologie Obstétrique II et Médecine de la Reproduction, CHU Cochin, Batiment Port Royal, 53, avenue de l’Observatoire, 75014 Paris, France; e-mail: charles.chapron@cch. aphp.fr. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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MD,
Bruno Borghese,
MD, PhD,
regression analysis, which adjusted for preoperative pain scores, age, body mass index, smoking habits, oral contraceptive pill use, infertility, and parity (adjusted odds ratio 2.96, 95% confidence interval 1.99–4.39; P,.001). The number of previous surgeries for endometriosis correlated significantly with lesion severity. Among women presenting with deeply infiltrating endometriosis (n5452), surgical history was significantly associated with a higher mean number of deeply infiltrating endometriosis lesions (3.161.9 compared with 2.661.8; P5.001) and with increased severity of deeply infiltrating endometriosis lesions, especially in the case of intestinal lesions (159 patients [66.0%] compared with 77 patients [37%], P,.001). CONCLUSION: A history of surgery for endometriosis correlates with the presence and severity of deeply infiltrating endometriosis, which underlines the necessity of a thorough preoperative assessment and a complete information of these patients before undertaking subsequent surgeries. (Obstet Gynecol 2014;124:709–17) DOI: 10.1097/AOG.0000000000000464
LEVEL OF EVIDENCE: II
E
ndometriosis, which is defined as the presence of endometrial-like tissue outside of the uterine cavity,1 is a public health issue that bears an important economic burden.2,3 It not only causes pain4 and infertility,5 but also has consequences related to medication, health care consumption, work absenteeism, impaired quality of life, and psychosocial factors.3 The pathogenesis of endometriosis remains unclear. However, anatomical distribution of endometriotic lesions supports the retrograde bleeding hypothesis,1,6 which theorizes that endometrial cells migrate through the fallopian tubes and implant into the abdominopelvic cavity, causing three types of endometriotic lesions: superficial
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endometriosis, ovarian endometrioma, or deeply infiltrating endometriosis. Diagnosis of endometriosis is difficult to establish with often a long delay since the onset of symptoms,7,8 especially in severe cases.9 It is now well established that surgery is efficient not only for managing pelvic pain10 and treatment of endometriosis-related infertility,5 but also for improving quality of life.11 Nevertheless, the benefits of surgery should not obscure the fact that this type of intervention can be associated with adverse outcomes.12 In fact, after surgery for ovarian endometrioma, patients have been shown to experience decreased levels of antimüllerian hormone, representing diminished ovarian reserve.13 Moreover, risk for complications after surgery for intestinal deeply infiltrating endometriosis has been correlated with disease dissemination, the total number of deeply infiltrating endometriosis lesions removed, or both.14 These observations suggest that early diagnosis, and thus reduced disease severity at treatment, should translate into less aggressive surgery and decreased risk for complications. Endometriosis has a high potential risk for recurrence,12 which many reports have attributed to incomplete surgical procedures.15,16 Although surgeons are more often faced with the clinical challenge of performing subsequent operations on endometriotic patients, very little is known about the characteristics of patients who have experienced previous surgical intervention for endometriosis and particularly on the surgical findings in the subsequent surgeries. The objective of this study was to determine whether a history of surgery could be considered as a marker for disease severity. To this end, we have compared endometriotic patients with and without a history of surgery for endometriosis who presented to our department with pain, infertility, or both. These individuals were treated by complete excision of all symptomatic endometriotic lesions.
MATERIALS AND METHODS Between January 2003 and August 2012 we conducted a cross-sectional study using a prospective database17 of all nonpregnant patients (younger than 42 years of age) undergoing surgery (laparotomy or laparoscopy) at our institution for benign gynecologic indications. All patients with histologically proven endometriosis could be included in the study. Patients visually diagnosed with endometriosis, but lacking histologic confirmation, were ineligible.17 In addition, those patients who refused to sign the consent form were excluded. Our institutional review board (Comité
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Consultatif de Protection des Personnes dans la Recherche Biomédicale) approved the study protocol. Histologically proven endometriotic lesions were classified into three groups: superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis.18 Endometriosis was considered as deeply infiltrating endometriosis when the muscularis (regardless of location: bladder, intestine, intrinsic ureter) was infiltrated by endometriotic tissue after radical surgery (eg, bowel resection, partial cystectomy, ureteral resection).19 For the other locations (ie, uterosacral ligament [s], extrinsic ureter, vagina), deeply infiltrating endometriosis was arbitrarily defined as endometriotic tissue infiltrating beneath the peritoneum surface deeper than 5 mm.20 Also, because the three types of endometriosis (superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis) are frequently associated,21 patients were classified according to their worst lesions. By definition, endometriotic lesions were ranked from least to most severe as follows: superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis.18 For analysis purposes, endometriotic patients were divided into two groups: group A (control group) included those without a history of surgery for endometriosis, and group B (study group) was comprised of patients who had received previous surgical intervention(s) for endometriosis. For each patient in group B, we collected the following information concerning the previous surgeries: total number of previous surgeries for endometriosis, among which number of previous surgeries for endometrioma, and surgical modalities (ie, transurethral resection, laparoscopy, and laparotomy). Because these various types of surgeries for endometriosis are commonly associated, patients were classified according to the most invasive surgical procedure performed. By definition, surgical procedures were ranked from least to most invasive as follows: transurethral resection, laparoscopy, and laparotomy. We did not routinely collect more detailed information about the previous procedures (not performed in our institution), ie, indications, precise surgical descriptions, and histologic conclusions. For each patient, data were collected during face-to-face interviews conducted by the surgeon in the month preceding surgery using a previously published questionnaire.17 The following data were collected: age (years), height (meters), weight (kilograms), body mass index (BMI, calculated as weight (kg)/ [height (m)]2), gravidity, parity, existence or duration of infertility (primary or secondary), painful symptoms, smoking habits, oral contraceptive pill (OCP) use, and various symptoms occurring during adolescence.
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Infertility was defined as having a 12-month history or longer of unprotected intercourse without pregnancy. In accordance with previous studies, “ever smoker” was defined as anyone who answered “yes” to the following question: “During your lifetime, have you smoked more than 100 cigarettes?” On the other hand, a “current smoker” was defined as a patient who answered “yes” to the following question: “Did you smoke a cigarette during the past 30 days?”17 As previously described, “current oral contraceptive use” was defined as OCP use for at least 6 months before surgery; “past oral contraceptive use” was defined as no OCP use for at least 6 months before surgery; other patients were classified as “never user of oral contraceptive.”22 Information regarding symptoms occurring during adolescence was also collected: 1) age at menarche; 2) amount of school absenteeism during menstruation; 3) history of fainting spells; and 4) whether OCP treatment was required for severe primary dysmenorrhea (age of first prescription and duration of use). The intensities of painful symptoms (eg, dysmenorrhea, deep dyspareunia, noncyclic chronic pelvic pain, gastrointestinal pain,14 and lower urinary tract pain) were evaluated preoperatively using a 10-cm visual analog scale. Comparisons between scores were performed, and second, for analysis purposes, patients were allocated into two groups according to intensity of preoperative pain (less than 7 or 7 or higher).23 For deeply patients with infiltrating endometriosis, severity was assessed based on two parameters,21 which were number of deeply infiltrating endometriosis lesions and location of the lesions. In the case of multiple sites, the patients were classified according to the worst finding (least to most severe: uterosacral, vagina, bladder, intestine, and ureter).24 During surgery, stages and mean scores (total, implants, adhesions) were assessed according to the American Society for Reproductive Medicine classification.25 Continuous data were presented as mean and standard deviations. Student’s t tests were used when appropriate, and categorical data were compared using x2 or Fisher’s exact tests. Association between presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped together) and history of previous surgery was studied using logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and a multivariable model was adjusted for factors found to be associated with deeply infiltrating endometriosis using bivariable analyses (P#.20). Missing date were excluded from multivariable analyses. All statistical tests were twosided and P,.05 was considered to be significant.
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No adjustment was used for multiple testing. Data were analyzed using Stata 11.0.
RESULTS During the study period, 780 patients underwent surgery for histologically proven endometriosis. Patient distribution according to worst endometriotic lesion was as follows: superficial endometriosis (131 patients [16.8%]), ovarian endometrioma (197 patients [25.3%]), and deeply infiltrating endometriosis (452 patients [57.9%]). Among the deeply infiltrating endometriosis patients, 170 (37.6%) were also diagnosed with ovarian endometrioma, for a total of 367 patients (47.0%) with endometrioma in the study population. Overall, 309 women (39.6%) presented with a history of surgical intervention for endometriosis. The majority of previous surgeries were performed through operative laparoscopy (235 patients [77.0%]). The number of previous surgeries was variable for patients, ranging from one to eight, and showed the following distribution: one (190 patients [61.5%]), two (73 patients [23.6%]), and three or more (46 patients [14.9%]). Also, the mean number of previous surgeries per patient was 1.660.9 (range 1–8). These operations were performed for ovarian endometrioma in 46.5% of the cases (n5139) with the mean number of surgeries for endometrioma per patient being 1.761.0 (range 1–5). Patient characteristics according to history of surgery for endometriosis are presented in Table 1. Differences were observed in age, gravidity, parity, OCP use, infertility (frequency and duration), intensity of preoperative painful symptoms, and adolescent factors (ie, school absenteeism, fainting spells during menstruation, and age at first OCP prescription for treating severe primary dysmenorrhea). Conversely, BMI, smoking habits, and age at menarche were not significantly different between the two groups. Additionally, we observed trends that indicated more OCP prescriptions for primary dysmenorrhea and longer duration of OCP use in those with a history of surgery, but they did not reach significance. In the entire study population (n5780), patients with a history of surgery (n5309) had an increased prevalence of deeply infiltrating endometriosis compared with women without previous surgical intervention for endometriosis (242 patients [78.3%] compared with 210 patients [44.6%]; P,.001) (Table 2). Using the American Society for Reproductive Medicine classification system, stage (P,.001), mean total (46.7634.0 compared with 28.2627.8), and mean adhesions (30.9627.0 compared with 14.1620.1) scores were significantly higher in the study group (Table 2).
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Table 1. Baseline Characteristics of Endometriotic Patients According to History of Previous Surgery for Endometriosis Patient Characteristics (N5780) Age (y) Height (cm) Weight (kg) BMI (kg/m2) Parity 0 1 2 or more Gravidity 0 1 2 or more Smoking habits Never smoker Ever smoker Current smoker OCP use Never user Ever user Current user Infertility Duration (mo) Preoperative painful symptoms scores†‡ Dysmenorrhea Less than 7 7 or higher Deep dyspareunia Less than 7 7 or higher Noncyclic chronic pelvic pain Less than 7 7 or higher Gastrointestinal symptoms Less than 7 7 or higher Lower urinary symptoms Less than 7 7 or higher Symptoms experienced during adolescence Age at menarche Absenteeism from school Fainting spells during menstruation Need to prescribe OCPs Age at first prescription Duration of use (mo)
No Previous Surgery (n5471)
Previous Surgery (n5309)
P*
31.165.3 165.166.6 62.3612.6 22.864.2
32.765.5 164.866.4 61.9613.8 22.663.9
,.001 .39 .58 .39
409 (86.8) 37 (7.9) 25 (5.3)
226 (73.1) 51 (16.5) 32 (10.4)
,.001
333 (70.7) 81 (17.2) 57 (12.1)
187 (60.5) 69 (22.3) 53 (17.2)
.01
247 (52.8) 65 (13.9) 156 (33.3)
182 (59.1) 38 (12.3) 88 (28.6)
.22
65 (13.9) 286 (61.1) 117 (25.0) 144 (31.0) 34.0628.1
19 (6.2) 238 (78.0) 48 (15.8) 128 (41.6) 53.0634.2
,.001
6.462.8 206 (43.8) 264 (56.2) 3.864.1 328 (74.2) 114 (25.8) 2.663.1 404 (86.0) 66 (14.0) 2.963.4 374 (79.6) 96 (20.4) 0.962.3 438 (93.2) 32 (6.8)
7.662.3 64 (21.0) 241 (79.0) 5.363.3 176 (58.5) 125 (41.5) 4.263.3 224 (72.7) 84 (27.3) 5.263.6 167 (54.2) 141 (45.8) 1.662.7 280 (90.9) 28 (9.1)
,.001 ,.001
13.061.6 140 (30.0) 59 (12.6) 93 (40.1) 19.269.7 8.665.0
12.861.6 116 (37.8) 56 (18.3) 71 (48.3) 17.863.0 9.465.0
.11 .025 .03 .12 .04 .31
.003 ,.001
,.001 ,.001 ,.001 ,.001 ,.001 ,.001 ,.001 .24
BMI, body mass index; OCP, oral contraceptive pill. Data are mean6standard deviation or n (%) unless otherwise specified. * Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. † Sometimes more than one for the same patient. ‡ Visual analog scale.
In the logistic regression multivariable model, history of previous surgery for endometriosis remained independently associated with presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped
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together; adjusted OR 2.96, 95% CI 1.99–4.39; P,.001) after adjustment for potential confounders. These included preoperative pain scores, age, BMI, smoking, OCP use, infertility history, and parity. In the multivariable model, other factors that remained
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Table 2. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to History of Previous Surgery for Endometriosis Surgical Findings (N5780) Mean ASRM scores‡ Total Implants Adherence ASRM stage‡ 1 2 3 4 Complete obliteration of pouch of Douglas Yes Endometriosis classificationk Superficial endometriosis Endometrioma Deeply infiltrating endometriosis Deeply infiltrating endometriosis only Deeply infiltrating endometriosis and endometrioma Total number of endometriomas Among deeply infiltrating endometriosis Mean number of deeply infiltrating endometriosis lesions Total no. of deeply infiltrating endometriosis lesions 1–2 3 or more Worst deeply infiltrating endometriosis lesion# Uterosacral ligament Vagina Bladder Intestine Ureter Multivariable analysis Endometriosis classification Deeply infiltrating endometriosis
No Previous Surgery (n5471)
Previous Surgery (n5309)
28.2627.8 14.4612.4 14.1620.1
46.7634.0 16.1612.8 30.9627.0
,.001 .07 ,.001
116 (24.7) 91 (19.4) 141 (30.0) 122 (26.0)
23 (7.5) 65 (21.1) 55 (17.9) 165 (53.6)
,.001 3.3 (2.4–4.5)§
76 (16.2)
133 (43.5)
4.0 (2.9–5.6)
109 (23.1) 152 (32.3) 210 (44.6) 144 (68.6) 66 (31.4)
22 (7.1) 45 (14.6) 242 (78.3) 138 (57.0) 104 (43.0)
4.5 (3.2–6.2)¶
218 (46.3)
149 (48.2)
1.1 (0.8–1.4)
2.661.8
3.161.9
130 (62.2) 79 (37.8)
107 (44.2) 135 (55.8)
71 (34.0) 21 (10.0) 18 (8.6) 77 (36.8) 22 (10.5)
32 (13.3) 16 (6.7) 17 (7.0) 159 (66.0) 17 (7.0)
P†
OR (95% CI)*
,.001 ,.001 .01
.60 ,.001
,.001 2.1 (1.4–3.0) ,.001 3.2 (2.1–4.8)**
2.96 (1.99–4.39)¶††
,.001
OR, odds ratio; CI, confidence interval; ASRM, American Society for Reproductive Medicine. Data are mean6standard deviation or n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Scores and stages according to the revised American Society for Reproductive Medicine classification.25 § Outcome variable5stage 4 compared with all other stages grouped together. k Endometriosis classification is defined as the least to most severe lesion; therefore, superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis add up to 100%, Among deeply infiltrating endometriosis, we differentiated those presenting with deeply infiltrating endometriosis only and those with deeply infiltrating endometriosis and ovarian endometrioma; these two groups add up to 100%. Finally, when adding patients with ovarian endometrioma only and with deeply infiltrating endometriosis and ovarian endometrioma, these numbers add up to the “total number of ovarian endometriomas” presented here. ¶ Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together. # According to a previously published surgical classification for deeply infiltrating endometriosis.24 ** Outcome variable5intestine and ureter compared with uterosacral ligament, vagina, and bladder grouped together. †† Adjusted OR obtained by multivariable logistic regression adjusted on preoperative pain scores, age, body mass index, smoking, oral contraceptive use, infertility history, and parity.
independently associated with the presence of deeply infiltrating endometriosis were all of the preoperative pain scores (except noncyclic chronic pelvic pain) and OCP use. Preoperative pain scores and previous sur-
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gery were therefore independent factors associated with deeply infiltrating endometriosis. The number of previous surgeries for endometriosis was significantly associated with disease severity (Table 2; Fig. 1). Patients
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with three or more previous surgeries for endometriosis (n546) were more likely to present with deeply infiltrating lesions and higher mean American Society for Reproductive Medicine scores; there was a trend toward a greater quantity of deeply infiltrating lesions and more intestinal deeply infiltrating endometriosis lesions in comparison to women with one to two previous surgeries (Table 3); however, neither reached significance (P5.07 and P5.11, respectively). The modality of prior surgery for endometriosis (ie, laparoscopy compared with laparotomy) did not seem to be associated with deeply infiltrating endometriosis prevalence (OR 0.6, 95% CI 0.3–1.2; P5.15). Furthermore, having a history of surgery for ovarian endometrioma (compared with other types of endometriosis surgery) was significantly correlated with a diagnosis of “ovarian endometrioma only” at the time of new surgery (Table 4; OR 2.5, 95% CI 1.3–5.0; P5.006). When we considered only those study participants who displayed deeply infiltrating endometriosis (n5452 patients), history of previous surgery for endometriosis was significantly associated with a higher mean number of deeply infiltrating lesions (3.161.9 compared with 2.661.8, P,.001) and more severe lesions, especially intestinal lesions (159 patients [66.0%] compared with 77 patients [37%]; P,.001) (Table 2).
DISCUSSION This cross-sectional study, using a large hospitalbased series of patients with histologically proven
endometriosis, found that patients presenting with a history of surgical intervention for endometriosis showed significantly more deeply infiltrating endometriosis than superficial endometriosis and ovarian endometrioma combined and more severe lesions (higher number of deeply infiltrating lesions and location with intestinal infiltration). Moreover, the mean number of previous surgeries for endometriosis correlated significantly with the presence and severity of deeply infiltrating endometriosis. Our results are in agreement with a recent Finnish study, which reported that patients with deep lesions had more often undergone previous surgeries for endometriosis. However, the significance of this previous finding was not confirmed by multivariate analysis, which may be the result of the small number of patients included in the study (n5201).26 “Recurrence or persistence?” remains a principal question. Our results raise the problem of whether endometriosis is in fact associated with a true recurrence rate (new lesions) or if second surgeries are only performed because of the persistence of painful symptoms resulting from an incomplete initial surgical procedure. Several studies have supported the idea that the best way to prevent recurrence is to perform complete initial surgeries by showing that risk of recurrence, notably concerning deep bladder and intestinal deeply infiltrating lesions, is significantly decreased in cases where initial surgeries are complete.14–16,19 With growing expertise in surgical procedures for endometriosis, there has been a reduction in the number of cases with incomplete removal, which has led to lower recurrence rates.27 Another argument
Fig. 1. Mean number of deep infiltrating endometrial lesions according to the number of previous surgeries for endometriosis. P,.001 for analysis of variance comparing number of deep infiltrating endometrial lesions according to number of previous surgeries. *P for pairwise testing compared with the control group (no prior surgeries for endometriosis); P,.001 for all tests. Sibiude. Previous Surgery and Severity of Endometriosis. Obstet Gynecol 2014.
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Table 3. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to Number of Previous Surgeries for Endometriosis or Type of Surgery Surgical Findings (N5309) Mean total ASRM scores‡ Endometriosis classification Superficial endometriosis Endometrioma Deeply infiltrating endometriosis Among deeply infiltrating endometriosis Total no. of deeply infiltrating endometriosis lesions 1–2 3 or more Worst deeply infiltrating endometriosis lesionk Uterosacral ligament Vagina Bladder Intestine Ureter
1 or 2 Surgeries (n5263)
3 or More Surgeries (n546)
44.9635.0
58.6624.5
.01
20 (7.6) 45 (17.1) 198 (75.3)
2 (4.3) 0 (0) 44 (95.7)
.005
93 (47.0) 105 (53.0)
14 (31.8) 30 (68.2)
28 (14.2) 14 (7.1) 17 (8.6) 123 (62.4) 15 (7.6)
4 2 0 36 2
(9.1) (4.6) (0) (81.8) (4.6)
OR (95% CI)*
P†
14.4 (2.0–106.9)§
.07 1.9 (0.9–3.8)
.11 1.7 (0.7–4.3)¶
OR, odds ratio; CI, confidence interval; ASRM, American Society for Reproductive Medicine. Data are mean6standard deviation or n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Scores and stages according to the revised American Society for Reproductive Medicine classification.25 § Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together. k According to a previously published surgical classification for deeply infiltrating endometriosis.24 ¶ Outcome variable5intestine and ureter compared with uterosacral ligament, vagina, and bladder grouped together.
supporting this theory is that the anatomical distribution of recurrent endometriotic lesions is often similar to that observed during the initial procedure.28 We observed that patients with a history of surgery for endometriosis when presenting at our institution also reported significantly higher rates of absenteeism from school during menstruation during the adolescent period and required more OCP prescriptions to treat severe primary dysmenorrhea. The fact that deeply infiltrating lesions can occur in young patients has already been reported in the literature,29 and our findings are in agreement with a previous study, which found that adolescent symptoms could be linked to future occurrence of deeply infiltrating lesions.18 Younger age at the time of surgery is associated with increased risk of recurrence,15 which could be explained by the reluctance of the surgeon to perform radical surgery on a young patient. This would support the theory of incomplete excision of lesions.21 Our study had several strengths: 1) a large number of endometriotic patients were enrolled in the study (n5780), and notably many severe forms of deeply infiltrating endometriosis (n5452), increasing statistical power. Endometriosis was histologically
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proven for each participant; 2) after surgery, patients were classified according to their most severe lesion (ranked from superficial endometriosis, ovarian endometrioma to deeply infiltrating endometriosis), which allowed us to analyze precisely association between history of endometriosis surgery and the worst endometriotic lesion; 3) clinical data were prospectively collected through questionnaires, which were identical for the control and study groups; 4) numerous parameters concerning sociodemographic, preoperative symptoms, and medical and surgical histories were collected for each patient, allowing us to make adjustments to limit confounding factors; 5) finally, this is a large study published on endometriotic patients presenting with a history of previous surgery (n5309). Our study also had some limitations. Because the majority of previous surgeries for endometriosis were not performed at our institution, one important limitation was that information regarding initial surgeries was not routinely available. It was therefore difficult to conclusively differentiate recurrence from a persistence of symptoms after an initial incomplete surgical procedure. In addition, recall bias could have influenced the validity of some of the data used in this
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Table 4. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to Type of Surgery Type of Previous Surgery Surgical Findings
Laparotomy Laparoscopy
Endometriosis classification Superficial endometriosis Endometrioma Deeply infiltrating endometriosis
n565 3 (4.6) 7 (10.8) 55 (84.6)
n5235 18 (7.7) 38 (16.2) 179 (76.1)
Other
Ovarian Endometrioma OR (95% CI)*
n5160 15 (9.4) 15 (9.4) 130 (81.2)
n5139 5 (3.6) 29 (20.9) 105 (75.5)
P† .005
2.5 (1.3–5.0)‡ 0.6 (0.3–1.2)§
.006 .15
OR, odds ratio; CI, confidence interval. Data are n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Outcome variable5ovarian endometrioma compared with superficial endometrosis and deeply infiltrating endometriosis grouped together. § Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together.
study. Indeed, although data were collected prospectively, some epidemiologic data were recounted long after the events had originally occurred (eg, adolescent period, smoking habits, OCP use). Another limit is the risk of false-positive associations resulting from multiple testing. We chose not to perform adjustments for multiple testing because such an approach is questionable from a methodologic standpoint30 and because the associations we observed were based hypotheses emanating from previous findings in the literature. Finally, we are a referral center for endometriosis management with a high proportion of severe patients. Thus, our results could be not applicable to other populations. We believe that our results are particularly relevant to the daily practice of gynecologists and surgeons. The decision to perform a second surgery for endometriosis is a difficult one. We show that, in this case, the practitioner could face a higher number of multifocal deeply infiltrating lesions with intestinal involvement. Our study underlines the necessity of a full preoperative radiologic assessment before deciding on a second surgery. Because clinical examination is of limited use for establishing the extent of the deeply infiltrating lesions, it is necessary to use noninvasive imaging processes before surgery. Transrectal ultrasonography was demonstrated to be efficient for the diagnosis of rectal wall infiltration by deeply infiltrating endometriosis lesions.31 Magnetic resonance imaging, also proposed, presents the great advantage of offering the possibility of obtaining a complete pelvic evaluation with a single imaging procedure.32 More recently, transvaginal ultrasonography has been found to be the method of choice, offering the advantages of accessibility and costeffectiveness as the first-line imaging process for patients presenting with clinically suspected deeply
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infiltrating endometriosis, because it demonstrates high accuracy in prediction of deep pelvic endometriosis in specific locations.33 Finally, repeated surgical interventions contribute to adhesion formation; we find that adhesion scores are significantly higher in patients with previous surgery. Adhesion formation greatly increases the difficulty of the procedure and the risk of incomplete surgery. REFERENCES 1. Sampson JA. Peritoneal endometriosis due to premenstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927;14:422–69. 2. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril 2006;86:1561–72. 3. Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011;96:366–373.e8. 4. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11:595–606. 5. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet 2010;376:730–8. 6. Bricou A, Batt RE, Chapron C. Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right. Eur J Obstet Gynecol Reprod Biol 2008;138: 127–34. 7. Husby GK, Haugen RS, Moen MH. Diagnostic delay in women with pain and endometriosis. Acta Obstet Gynecol Scand 2003;82:649–53. 8. Greene R, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertil Steril 2009;91:32–9. 9. Matsuzaki S, Canis M, Pouly J-L, Rabischong B, Botchorishvili R, Mage G. Relationship between delay of surgical diagnosis and severity of disease in patients with symptomatic deep infiltrating endometriosis. Fertil Steril 2006;86:1314–6. 10. Hart RJ, Hickey M, Maouris P, Buckett W, Garry R. Excisional surgery versus ablative surgery for ovarian endometriomata.
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The Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD004992. DOI: 10.1002/14651858.CD004992. pub2. 11. Meuleman C, Tomassetti C, D’Hooghe TM. Clinical outcome after laparoscopic radical excision of endometriosis and laparoscopic segmental bowel resection. Curr Opin Obstet Gynecol 2012;24:245–52. 12. Vercellini P, Crosignani PG, Abbiati A, Somigliana E, Viganò P, Fedele L, et al. The effect of surgery for symptomatic endometriosis: the other side of the story. Hum Reprod Update 2009;15:177–88. 13. Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012;97:3146–54. 14. Dousset B, Leconte M, Borghese B, Millischer AE, Roseau G, Arkwright S, et al. Complete surgery for low rectal endometriosis: long-term results of a 100-case prospective study. Ann Surg 2010;251:887–95. 15. Vignali M, Bianchi S, Candiani M, Spadaccini G, Oggioni G, Busacca M. Surgical treatment of deep endometriosis and risk of recurrence. J Minim Invasive Gynecol 2005;12:508–13. 16. Fedele L, Bianchi S, Zanconato G, Berlanda N, Borruto F, Frontino G. Tailoring radicality in demolitive surgery for deeply infiltrating endometriosis. Am J Obstet Gynecol 2005;193:114–7. 17. Chapron C, Souza C, de Ziegler D, Lafay-Pillet MC, Ngô C, Bijaoui G, et al. Smoking habits of 411 women with histologically proven endometriosis and 567 unaffected women. Fertil Steril 2010;94:2353–5. 18. Chapron C, Lafay-Pillet MC, Monceau E, Borghese B, Ngô C, Souza C, et al. Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis. Fertil Steril 2011;95:877–81. 19. Chapron C, Bourret A, Chopin N, Dousset B, Leconte M, Amsellem-Ouazana D, et al. Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions. Hum Reprod 2010;25:884–9. 20. Koninckx PR, Martin DC. Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa? Fertil Steril 1992;58:924–8. 21. Chapron C, Pietin-Vialle C, Borghese B, Davy C, Foulot H, Chopin N. Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis. Fertil Steril 2009;92:453–7.
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22. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod 2011;26:2028–35. 23. Chapron C, Santulli P, de Ziegler D, Noel J-C, Anaf V, Streuli I, et al. Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis. Hum Reprod 2012;27:702–11. 24. Chapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-Lavenu MC, et al. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Hum Reprod 2006;21:1839–45. 25. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817–21. 26. Setälä M, Savolainen H, Kossi J, Ranta T, Mäkinen J. Deeply infiltrating disease in surgically treated endometriosis patients. Acta Obstet Gynecol Scand 2011;90:468–72. 27. Carmona F, Martínez-Zamora A, González X, Ginés A, Buñesch L, Balasch J. Does the learning curve of conservative laparoscopic surgery in women with rectovaginal endometriosis impair the recurrence rate? Fertil Steril 2009;92:868–75. 28. Taylor E, Williams C. Surgical treatment of endometriosis: location and patterns of disease at reoperation. Fertil Steril 2010;93:57–61. 29. Vercellini P, Aimi G, Panazza S, Vicentini S, Pisacreta A, Crosignani PG. Deep endometriosis conundrum: evidence in favor of a peritoneal origin. Fertil Steril 2000;73:1043–6. 30. Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990;1:43–6. 31. Bazot M, Bornier C, Dubernard G, Roseau G, Cortez A, Daraï E. Accuracy of magnetic resonance imaging and rectal endoscopic sonography for the prediction of location of deep pelvic endometriosis. Hum Reprod 2007;22:1457–63. 32. Bazot M, Darai E, Hourani R, Thomassin I, Cortez A, Uzan S, et al. Deep pelvic endometriosis: MR imaging for diagnosis and prediction of extension of disease. Radiology 2004;232: 379–89. 33. Piketty M, Chopin N, Dousset B, Millischer-Bellaische A-E, Roseau G, Leconte M, et al. Preoperative work-up for patients with deeply infiltrating endometriosis: transvaginal ultrasonography must definitely be the first-line imaging examination. Hum Reprod 2009;24:602–7.
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Association of History of Surgery for Endometriosis With Severity of Deeply Infiltrating Endometriosis Jeanne Sibiude, MD, Pietro Santulli, MD, PhD, Louis Marcellin, Bertrand Dousset, MD, and Charles Chapron, MD OBJECTIVE: To assess whether a history of surgery for endometriosis could be considered as a marker for disease severity. METHODS: This cross-sectional study included 780 women with histologically proven endometriosis who underwent surgery. We compared 309 patients with a history of surgery for endometriosis (study group) with 471 patients who did not receive prior surgical intervention (control group). Multivariate logistic regression was performed to assess the risk of deeply infiltrating endometriosis (defined by invasion of the muscularis by endometriotic tissue). RESULTS: Patients with a history of surgery displayed an increased prevalence of deeply infiltrating endometriosis (242 patients [78.3%] compared with 210 patients [44.6%], respectively; P,.001). Moreover, the study group showed significantly higher stage, mean total (P,.001), and mean adhesions (P,.001) scores based on the American Society for Reproductive Medicine classification system. Furthermore, history of previous surgery remained independently associated with the presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped together) in multivariate From the Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Inserm, Unité de Recherche U1016, Université Paris Descartes, Faculté de Médecine, EA 1833, ERTi, AP-HP, CHU cochin, and Université Paris Descartes, Faculté de Médecine, Assistance Publique—Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, Department of Digestive and Endocrine Surgery, Paris, France. The authors thank surgeons from the department for their expert assistance with data collection and Nathalie Girma for unabatedly managing the database. Corresponding author: Charles Chapron, MD, Service de Gynécologie Obstétrique II et Médecine de la Reproduction, CHU Cochin, Batiment Port Royal, 53, avenue de l’Observatoire, 75014 Paris, France; e-mail: charles.chapron@cch. aphp.fr. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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MD,
Bruno Borghese,
MD, PhD,
regression analysis, which adjusted for preoperative pain scores, age, body mass index, smoking habits, oral contraceptive pill use, infertility, and parity (adjusted odds ratio 2.96, 95% confidence interval 1.99–4.39; P,.001). The number of previous surgeries for endometriosis correlated significantly with lesion severity. Among women presenting with deeply infiltrating endometriosis (n5452), surgical history was significantly associated with a higher mean number of deeply infiltrating endometriosis lesions (3.161.9 compared with 2.661.8; P5.001) and with increased severity of deeply infiltrating endometriosis lesions, especially in the case of intestinal lesions (159 patients [66.0%] compared with 77 patients [37%], P,.001). CONCLUSION: A history of surgery for endometriosis correlates with the presence and severity of deeply infiltrating endometriosis, which underlines the necessity of a thorough preoperative assessment and a complete information of these patients before undertaking subsequent surgeries. (Obstet Gynecol 2014;124:709–17) DOI: 10.1097/AOG.0000000000000464
LEVEL OF EVIDENCE: II
E
ndometriosis, which is defined as the presence of endometrial-like tissue outside of the uterine cavity,1 is a public health issue that bears an important economic burden.2,3 It not only causes pain4 and infertility,5 but also has consequences related to medication, health care consumption, work absenteeism, impaired quality of life, and psychosocial factors.3 The pathogenesis of endometriosis remains unclear. However, anatomical distribution of endometriotic lesions supports the retrograde bleeding hypothesis,1,6 which theorizes that endometrial cells migrate through the fallopian tubes and implant into the abdominopelvic cavity, causing three types of endometriotic lesions: superficial
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endometriosis, ovarian endometrioma, or deeply infiltrating endometriosis. Diagnosis of endometriosis is difficult to establish with often a long delay since the onset of symptoms,7,8 especially in severe cases.9 It is now well established that surgery is efficient not only for managing pelvic pain10 and treatment of endometriosis-related infertility,5 but also for improving quality of life.11 Nevertheless, the benefits of surgery should not obscure the fact that this type of intervention can be associated with adverse outcomes.12 In fact, after surgery for ovarian endometrioma, patients have been shown to experience decreased levels of antimüllerian hormone, representing diminished ovarian reserve.13 Moreover, risk for complications after surgery for intestinal deeply infiltrating endometriosis has been correlated with disease dissemination, the total number of deeply infiltrating endometriosis lesions removed, or both.14 These observations suggest that early diagnosis, and thus reduced disease severity at treatment, should translate into less aggressive surgery and decreased risk for complications. Endometriosis has a high potential risk for recurrence,12 which many reports have attributed to incomplete surgical procedures.15,16 Although surgeons are more often faced with the clinical challenge of performing subsequent operations on endometriotic patients, very little is known about the characteristics of patients who have experienced previous surgical intervention for endometriosis and particularly on the surgical findings in the subsequent surgeries. The objective of this study was to determine whether a history of surgery could be considered as a marker for disease severity. To this end, we have compared endometriotic patients with and without a history of surgery for endometriosis who presented to our department with pain, infertility, or both. These individuals were treated by complete excision of all symptomatic endometriotic lesions.
MATERIALS AND METHODS Between January 2003 and August 2012 we conducted a cross-sectional study using a prospective database17 of all nonpregnant patients (younger than 42 years of age) undergoing surgery (laparotomy or laparoscopy) at our institution for benign gynecologic indications. All patients with histologically proven endometriosis could be included in the study. Patients visually diagnosed with endometriosis, but lacking histologic confirmation, were ineligible.17 In addition, those patients who refused to sign the consent form were excluded. Our institutional review board (Comité
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Consultatif de Protection des Personnes dans la Recherche Biomédicale) approved the study protocol. Histologically proven endometriotic lesions were classified into three groups: superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis.18 Endometriosis was considered as deeply infiltrating endometriosis when the muscularis (regardless of location: bladder, intestine, intrinsic ureter) was infiltrated by endometriotic tissue after radical surgery (eg, bowel resection, partial cystectomy, ureteral resection).19 For the other locations (ie, uterosacral ligament [s], extrinsic ureter, vagina), deeply infiltrating endometriosis was arbitrarily defined as endometriotic tissue infiltrating beneath the peritoneum surface deeper than 5 mm.20 Also, because the three types of endometriosis (superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis) are frequently associated,21 patients were classified according to their worst lesions. By definition, endometriotic lesions were ranked from least to most severe as follows: superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis.18 For analysis purposes, endometriotic patients were divided into two groups: group A (control group) included those without a history of surgery for endometriosis, and group B (study group) was comprised of patients who had received previous surgical intervention(s) for endometriosis. For each patient in group B, we collected the following information concerning the previous surgeries: total number of previous surgeries for endometriosis, among which number of previous surgeries for endometrioma, and surgical modalities (ie, transurethral resection, laparoscopy, and laparotomy). Because these various types of surgeries for endometriosis are commonly associated, patients were classified according to the most invasive surgical procedure performed. By definition, surgical procedures were ranked from least to most invasive as follows: transurethral resection, laparoscopy, and laparotomy. We did not routinely collect more detailed information about the previous procedures (not performed in our institution), ie, indications, precise surgical descriptions, and histologic conclusions. For each patient, data were collected during face-to-face interviews conducted by the surgeon in the month preceding surgery using a previously published questionnaire.17 The following data were collected: age (years), height (meters), weight (kilograms), body mass index (BMI, calculated as weight (kg)/ [height (m)]2), gravidity, parity, existence or duration of infertility (primary or secondary), painful symptoms, smoking habits, oral contraceptive pill (OCP) use, and various symptoms occurring during adolescence.
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Infertility was defined as having a 12-month history or longer of unprotected intercourse without pregnancy. In accordance with previous studies, “ever smoker” was defined as anyone who answered “yes” to the following question: “During your lifetime, have you smoked more than 100 cigarettes?” On the other hand, a “current smoker” was defined as a patient who answered “yes” to the following question: “Did you smoke a cigarette during the past 30 days?”17 As previously described, “current oral contraceptive use” was defined as OCP use for at least 6 months before surgery; “past oral contraceptive use” was defined as no OCP use for at least 6 months before surgery; other patients were classified as “never user of oral contraceptive.”22 Information regarding symptoms occurring during adolescence was also collected: 1) age at menarche; 2) amount of school absenteeism during menstruation; 3) history of fainting spells; and 4) whether OCP treatment was required for severe primary dysmenorrhea (age of first prescription and duration of use). The intensities of painful symptoms (eg, dysmenorrhea, deep dyspareunia, noncyclic chronic pelvic pain, gastrointestinal pain,14 and lower urinary tract pain) were evaluated preoperatively using a 10-cm visual analog scale. Comparisons between scores were performed, and second, for analysis purposes, patients were allocated into two groups according to intensity of preoperative pain (less than 7 or 7 or higher).23 For deeply patients with infiltrating endometriosis, severity was assessed based on two parameters,21 which were number of deeply infiltrating endometriosis lesions and location of the lesions. In the case of multiple sites, the patients were classified according to the worst finding (least to most severe: uterosacral, vagina, bladder, intestine, and ureter).24 During surgery, stages and mean scores (total, implants, adhesions) were assessed according to the American Society for Reproductive Medicine classification.25 Continuous data were presented as mean and standard deviations. Student’s t tests were used when appropriate, and categorical data were compared using x2 or Fisher’s exact tests. Association between presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped together) and history of previous surgery was studied using logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and a multivariable model was adjusted for factors found to be associated with deeply infiltrating endometriosis using bivariable analyses (P#.20). Missing date were excluded from multivariable analyses. All statistical tests were twosided and P,.05 was considered to be significant.
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No adjustment was used for multiple testing. Data were analyzed using Stata 11.0.
RESULTS During the study period, 780 patients underwent surgery for histologically proven endometriosis. Patient distribution according to worst endometriotic lesion was as follows: superficial endometriosis (131 patients [16.8%]), ovarian endometrioma (197 patients [25.3%]), and deeply infiltrating endometriosis (452 patients [57.9%]). Among the deeply infiltrating endometriosis patients, 170 (37.6%) were also diagnosed with ovarian endometrioma, for a total of 367 patients (47.0%) with endometrioma in the study population. Overall, 309 women (39.6%) presented with a history of surgical intervention for endometriosis. The majority of previous surgeries were performed through operative laparoscopy (235 patients [77.0%]). The number of previous surgeries was variable for patients, ranging from one to eight, and showed the following distribution: one (190 patients [61.5%]), two (73 patients [23.6%]), and three or more (46 patients [14.9%]). Also, the mean number of previous surgeries per patient was 1.660.9 (range 1–8). These operations were performed for ovarian endometrioma in 46.5% of the cases (n5139) with the mean number of surgeries for endometrioma per patient being 1.761.0 (range 1–5). Patient characteristics according to history of surgery for endometriosis are presented in Table 1. Differences were observed in age, gravidity, parity, OCP use, infertility (frequency and duration), intensity of preoperative painful symptoms, and adolescent factors (ie, school absenteeism, fainting spells during menstruation, and age at first OCP prescription for treating severe primary dysmenorrhea). Conversely, BMI, smoking habits, and age at menarche were not significantly different between the two groups. Additionally, we observed trends that indicated more OCP prescriptions for primary dysmenorrhea and longer duration of OCP use in those with a history of surgery, but they did not reach significance. In the entire study population (n5780), patients with a history of surgery (n5309) had an increased prevalence of deeply infiltrating endometriosis compared with women without previous surgical intervention for endometriosis (242 patients [78.3%] compared with 210 patients [44.6%]; P,.001) (Table 2). Using the American Society for Reproductive Medicine classification system, stage (P,.001), mean total (46.7634.0 compared with 28.2627.8), and mean adhesions (30.9627.0 compared with 14.1620.1) scores were significantly higher in the study group (Table 2).
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Table 1. Baseline Characteristics of Endometriotic Patients According to History of Previous Surgery for Endometriosis Patient Characteristics (N5780) Age (y) Height (cm) Weight (kg) BMI (kg/m2) Parity 0 1 2 or more Gravidity 0 1 2 or more Smoking habits Never smoker Ever smoker Current smoker OCP use Never user Ever user Current user Infertility Duration (mo) Preoperative painful symptoms scores†‡ Dysmenorrhea Less than 7 7 or higher Deep dyspareunia Less than 7 7 or higher Noncyclic chronic pelvic pain Less than 7 7 or higher Gastrointestinal symptoms Less than 7 7 or higher Lower urinary symptoms Less than 7 7 or higher Symptoms experienced during adolescence Age at menarche Absenteeism from school Fainting spells during menstruation Need to prescribe OCPs Age at first prescription Duration of use (mo)
No Previous Surgery (n5471)
Previous Surgery (n5309)
P*
31.165.3 165.166.6 62.3612.6 22.864.2
32.765.5 164.866.4 61.9613.8 22.663.9
,.001 .39 .58 .39
409 (86.8) 37 (7.9) 25 (5.3)
226 (73.1) 51 (16.5) 32 (10.4)
,.001
333 (70.7) 81 (17.2) 57 (12.1)
187 (60.5) 69 (22.3) 53 (17.2)
.01
247 (52.8) 65 (13.9) 156 (33.3)
182 (59.1) 38 (12.3) 88 (28.6)
.22
65 (13.9) 286 (61.1) 117 (25.0) 144 (31.0) 34.0628.1
19 (6.2) 238 (78.0) 48 (15.8) 128 (41.6) 53.0634.2
,.001
6.462.8 206 (43.8) 264 (56.2) 3.864.1 328 (74.2) 114 (25.8) 2.663.1 404 (86.0) 66 (14.0) 2.963.4 374 (79.6) 96 (20.4) 0.962.3 438 (93.2) 32 (6.8)
7.662.3 64 (21.0) 241 (79.0) 5.363.3 176 (58.5) 125 (41.5) 4.263.3 224 (72.7) 84 (27.3) 5.263.6 167 (54.2) 141 (45.8) 1.662.7 280 (90.9) 28 (9.1)
,.001 ,.001
13.061.6 140 (30.0) 59 (12.6) 93 (40.1) 19.269.7 8.665.0
12.861.6 116 (37.8) 56 (18.3) 71 (48.3) 17.863.0 9.465.0
.11 .025 .03 .12 .04 .31
.003 ,.001
,.001 ,.001 ,.001 ,.001 ,.001 ,.001 ,.001 .24
BMI, body mass index; OCP, oral contraceptive pill. Data are mean6standard deviation or n (%) unless otherwise specified. * Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. † Sometimes more than one for the same patient. ‡ Visual analog scale.
In the logistic regression multivariable model, history of previous surgery for endometriosis remained independently associated with presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped
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together; adjusted OR 2.96, 95% CI 1.99–4.39; P,.001) after adjustment for potential confounders. These included preoperative pain scores, age, BMI, smoking, OCP use, infertility history, and parity. In the multivariable model, other factors that remained
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Table 2. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to History of Previous Surgery for Endometriosis Surgical Findings (N5780) Mean ASRM scores‡ Total Implants Adherence ASRM stage‡ 1 2 3 4 Complete obliteration of pouch of Douglas Yes Endometriosis classificationk Superficial endometriosis Endometrioma Deeply infiltrating endometriosis Deeply infiltrating endometriosis only Deeply infiltrating endometriosis and endometrioma Total number of endometriomas Among deeply infiltrating endometriosis Mean number of deeply infiltrating endometriosis lesions Total no. of deeply infiltrating endometriosis lesions 1–2 3 or more Worst deeply infiltrating endometriosis lesion# Uterosacral ligament Vagina Bladder Intestine Ureter Multivariable analysis Endometriosis classification Deeply infiltrating endometriosis
No Previous Surgery (n5471)
Previous Surgery (n5309)
28.2627.8 14.4612.4 14.1620.1
46.7634.0 16.1612.8 30.9627.0
,.001 .07 ,.001
116 (24.7) 91 (19.4) 141 (30.0) 122 (26.0)
23 (7.5) 65 (21.1) 55 (17.9) 165 (53.6)
,.001 3.3 (2.4–4.5)§
76 (16.2)
133 (43.5)
4.0 (2.9–5.6)
109 (23.1) 152 (32.3) 210 (44.6) 144 (68.6) 66 (31.4)
22 (7.1) 45 (14.6) 242 (78.3) 138 (57.0) 104 (43.0)
4.5 (3.2–6.2)¶
218 (46.3)
149 (48.2)
1.1 (0.8–1.4)
2.661.8
3.161.9
130 (62.2) 79 (37.8)
107 (44.2) 135 (55.8)
71 (34.0) 21 (10.0) 18 (8.6) 77 (36.8) 22 (10.5)
32 (13.3) 16 (6.7) 17 (7.0) 159 (66.0) 17 (7.0)
P†
OR (95% CI)*
,.001 ,.001 .01
.60 ,.001
,.001 2.1 (1.4–3.0) ,.001 3.2 (2.1–4.8)**
2.96 (1.99–4.39)¶††
,.001
OR, odds ratio; CI, confidence interval; ASRM, American Society for Reproductive Medicine. Data are mean6standard deviation or n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Scores and stages according to the revised American Society for Reproductive Medicine classification.25 § Outcome variable5stage 4 compared with all other stages grouped together. k Endometriosis classification is defined as the least to most severe lesion; therefore, superficial endometriosis, ovarian endometrioma, and deeply infiltrating endometriosis add up to 100%, Among deeply infiltrating endometriosis, we differentiated those presenting with deeply infiltrating endometriosis only and those with deeply infiltrating endometriosis and ovarian endometrioma; these two groups add up to 100%. Finally, when adding patients with ovarian endometrioma only and with deeply infiltrating endometriosis and ovarian endometrioma, these numbers add up to the “total number of ovarian endometriomas” presented here. ¶ Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together. # According to a previously published surgical classification for deeply infiltrating endometriosis.24 ** Outcome variable5intestine and ureter compared with uterosacral ligament, vagina, and bladder grouped together. †† Adjusted OR obtained by multivariable logistic regression adjusted on preoperative pain scores, age, body mass index, smoking, oral contraceptive use, infertility history, and parity.
independently associated with the presence of deeply infiltrating endometriosis were all of the preoperative pain scores (except noncyclic chronic pelvic pain) and OCP use. Preoperative pain scores and previous sur-
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gery were therefore independent factors associated with deeply infiltrating endometriosis. The number of previous surgeries for endometriosis was significantly associated with disease severity (Table 2; Fig. 1). Patients
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with three or more previous surgeries for endometriosis (n546) were more likely to present with deeply infiltrating lesions and higher mean American Society for Reproductive Medicine scores; there was a trend toward a greater quantity of deeply infiltrating lesions and more intestinal deeply infiltrating endometriosis lesions in comparison to women with one to two previous surgeries (Table 3); however, neither reached significance (P5.07 and P5.11, respectively). The modality of prior surgery for endometriosis (ie, laparoscopy compared with laparotomy) did not seem to be associated with deeply infiltrating endometriosis prevalence (OR 0.6, 95% CI 0.3–1.2; P5.15). Furthermore, having a history of surgery for ovarian endometrioma (compared with other types of endometriosis surgery) was significantly correlated with a diagnosis of “ovarian endometrioma only” at the time of new surgery (Table 4; OR 2.5, 95% CI 1.3–5.0; P5.006). When we considered only those study participants who displayed deeply infiltrating endometriosis (n5452 patients), history of previous surgery for endometriosis was significantly associated with a higher mean number of deeply infiltrating lesions (3.161.9 compared with 2.661.8, P,.001) and more severe lesions, especially intestinal lesions (159 patients [66.0%] compared with 77 patients [37%]; P,.001) (Table 2).
DISCUSSION This cross-sectional study, using a large hospitalbased series of patients with histologically proven
endometriosis, found that patients presenting with a history of surgical intervention for endometriosis showed significantly more deeply infiltrating endometriosis than superficial endometriosis and ovarian endometrioma combined and more severe lesions (higher number of deeply infiltrating lesions and location with intestinal infiltration). Moreover, the mean number of previous surgeries for endometriosis correlated significantly with the presence and severity of deeply infiltrating endometriosis. Our results are in agreement with a recent Finnish study, which reported that patients with deep lesions had more often undergone previous surgeries for endometriosis. However, the significance of this previous finding was not confirmed by multivariate analysis, which may be the result of the small number of patients included in the study (n5201).26 “Recurrence or persistence?” remains a principal question. Our results raise the problem of whether endometriosis is in fact associated with a true recurrence rate (new lesions) or if second surgeries are only performed because of the persistence of painful symptoms resulting from an incomplete initial surgical procedure. Several studies have supported the idea that the best way to prevent recurrence is to perform complete initial surgeries by showing that risk of recurrence, notably concerning deep bladder and intestinal deeply infiltrating lesions, is significantly decreased in cases where initial surgeries are complete.14–16,19 With growing expertise in surgical procedures for endometriosis, there has been a reduction in the number of cases with incomplete removal, which has led to lower recurrence rates.27 Another argument
Fig. 1. Mean number of deep infiltrating endometrial lesions according to the number of previous surgeries for endometriosis. P,.001 for analysis of variance comparing number of deep infiltrating endometrial lesions according to number of previous surgeries. *P for pairwise testing compared with the control group (no prior surgeries for endometriosis); P,.001 for all tests. Sibiude. Previous Surgery and Severity of Endometriosis. Obstet Gynecol 2014.
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Table 3. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to Number of Previous Surgeries for Endometriosis or Type of Surgery Surgical Findings (N5309) Mean total ASRM scores‡ Endometriosis classification Superficial endometriosis Endometrioma Deeply infiltrating endometriosis Among deeply infiltrating endometriosis Total no. of deeply infiltrating endometriosis lesions 1–2 3 or more Worst deeply infiltrating endometriosis lesionk Uterosacral ligament Vagina Bladder Intestine Ureter
1 or 2 Surgeries (n5263)
3 or More Surgeries (n546)
44.9635.0
58.6624.5
.01
20 (7.6) 45 (17.1) 198 (75.3)
2 (4.3) 0 (0) 44 (95.7)
.005
93 (47.0) 105 (53.0)
14 (31.8) 30 (68.2)
28 (14.2) 14 (7.1) 17 (8.6) 123 (62.4) 15 (7.6)
4 2 0 36 2
(9.1) (4.6) (0) (81.8) (4.6)
OR (95% CI)*
P†
14.4 (2.0–106.9)§
.07 1.9 (0.9–3.8)
.11 1.7 (0.7–4.3)¶
OR, odds ratio; CI, confidence interval; ASRM, American Society for Reproductive Medicine. Data are mean6standard deviation or n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Scores and stages according to the revised American Society for Reproductive Medicine classification.25 § Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together. k According to a previously published surgical classification for deeply infiltrating endometriosis.24 ¶ Outcome variable5intestine and ureter compared with uterosacral ligament, vagina, and bladder grouped together.
supporting this theory is that the anatomical distribution of recurrent endometriotic lesions is often similar to that observed during the initial procedure.28 We observed that patients with a history of surgery for endometriosis when presenting at our institution also reported significantly higher rates of absenteeism from school during menstruation during the adolescent period and required more OCP prescriptions to treat severe primary dysmenorrhea. The fact that deeply infiltrating lesions can occur in young patients has already been reported in the literature,29 and our findings are in agreement with a previous study, which found that adolescent symptoms could be linked to future occurrence of deeply infiltrating lesions.18 Younger age at the time of surgery is associated with increased risk of recurrence,15 which could be explained by the reluctance of the surgeon to perform radical surgery on a young patient. This would support the theory of incomplete excision of lesions.21 Our study had several strengths: 1) a large number of endometriotic patients were enrolled in the study (n5780), and notably many severe forms of deeply infiltrating endometriosis (n5452), increasing statistical power. Endometriosis was histologically
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proven for each participant; 2) after surgery, patients were classified according to their most severe lesion (ranked from superficial endometriosis, ovarian endometrioma to deeply infiltrating endometriosis), which allowed us to analyze precisely association between history of endometriosis surgery and the worst endometriotic lesion; 3) clinical data were prospectively collected through questionnaires, which were identical for the control and study groups; 4) numerous parameters concerning sociodemographic, preoperative symptoms, and medical and surgical histories were collected for each patient, allowing us to make adjustments to limit confounding factors; 5) finally, this is a large study published on endometriotic patients presenting with a history of previous surgery (n5309). Our study also had some limitations. Because the majority of previous surgeries for endometriosis were not performed at our institution, one important limitation was that information regarding initial surgeries was not routinely available. It was therefore difficult to conclusively differentiate recurrence from a persistence of symptoms after an initial incomplete surgical procedure. In addition, recall bias could have influenced the validity of some of the data used in this
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Table 4. Histologic Classification and Characteristics of Deeply Infiltrating Endometriosis According to Type of Surgery Type of Previous Surgery Surgical Findings
Laparotomy Laparoscopy
Endometriosis classification Superficial endometriosis Endometrioma Deeply infiltrating endometriosis
n565 3 (4.6) 7 (10.8) 55 (84.6)
n5235 18 (7.7) 38 (16.2) 179 (76.1)
Other
Ovarian Endometrioma OR (95% CI)*
n5160 15 (9.4) 15 (9.4) 130 (81.2)
n5139 5 (3.6) 29 (20.9) 105 (75.5)
P† .005
2.5 (1.3–5.0)‡ 0.6 (0.3–1.2)§
.006 .15
OR, odds ratio; CI, confidence interval. Data are n (%) unless otherwise specified. * OR obtained by bivariable logistic regression comparing patients with previous surgery to patients without previous surgery (reference). † Statistical tests used as appropriate, Student’s t test for continuous variables, and x2 or Fisher’s exact test for categorical variables. ‡ Outcome variable5ovarian endometrioma compared with superficial endometrosis and deeply infiltrating endometriosis grouped together. § Outcome variable5deeply infiltrating endometriosis compared with superficial endometriosis and ovarian endometrioma grouped together.
study. Indeed, although data were collected prospectively, some epidemiologic data were recounted long after the events had originally occurred (eg, adolescent period, smoking habits, OCP use). Another limit is the risk of false-positive associations resulting from multiple testing. We chose not to perform adjustments for multiple testing because such an approach is questionable from a methodologic standpoint30 and because the associations we observed were based hypotheses emanating from previous findings in the literature. Finally, we are a referral center for endometriosis management with a high proportion of severe patients. Thus, our results could be not applicable to other populations. We believe that our results are particularly relevant to the daily practice of gynecologists and surgeons. The decision to perform a second surgery for endometriosis is a difficult one. We show that, in this case, the practitioner could face a higher number of multifocal deeply infiltrating lesions with intestinal involvement. Our study underlines the necessity of a full preoperative radiologic assessment before deciding on a second surgery. Because clinical examination is of limited use for establishing the extent of the deeply infiltrating lesions, it is necessary to use noninvasive imaging processes before surgery. Transrectal ultrasonography was demonstrated to be efficient for the diagnosis of rectal wall infiltration by deeply infiltrating endometriosis lesions.31 Magnetic resonance imaging, also proposed, presents the great advantage of offering the possibility of obtaining a complete pelvic evaluation with a single imaging procedure.32 More recently, transvaginal ultrasonography has been found to be the method of choice, offering the advantages of accessibility and costeffectiveness as the first-line imaging process for patients presenting with clinically suspected deeply
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infiltrating endometriosis, because it demonstrates high accuracy in prediction of deep pelvic endometriosis in specific locations.33 Finally, repeated surgical interventions contribute to adhesion formation; we find that adhesion scores are significantly higher in patients with previous surgery. Adhesion formation greatly increases the difficulty of the procedure and the risk of incomplete surgery. REFERENCES 1. Sampson JA. Peritoneal endometriosis due to premenstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927;14:422–69. 2. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril 2006;86:1561–72. 3. Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011;96:366–373.e8. 4. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11:595–606. 5. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet 2010;376:730–8. 6. Bricou A, Batt RE, Chapron C. Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right. Eur J Obstet Gynecol Reprod Biol 2008;138: 127–34. 7. Husby GK, Haugen RS, Moen MH. Diagnostic delay in women with pain and endometriosis. Acta Obstet Gynecol Scand 2003;82:649–53. 8. Greene R, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertil Steril 2009;91:32–9. 9. Matsuzaki S, Canis M, Pouly J-L, Rabischong B, Botchorishvili R, Mage G. Relationship between delay of surgical diagnosis and severity of disease in patients with symptomatic deep infiltrating endometriosis. Fertil Steril 2006;86:1314–6. 10. Hart RJ, Hickey M, Maouris P, Buckett W, Garry R. Excisional surgery versus ablative surgery for ovarian endometriomata.
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22. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod 2011;26:2028–35. 23. Chapron C, Santulli P, de Ziegler D, Noel J-C, Anaf V, Streuli I, et al. Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis. Hum Reprod 2012;27:702–11. 24. Chapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-Lavenu MC, et al. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Hum Reprod 2006;21:1839–45. 25. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817–21. 26. Setälä M, Savolainen H, Kossi J, Ranta T, Mäkinen J. Deeply infiltrating disease in surgically treated endometriosis patients. Acta Obstet Gynecol Scand 2011;90:468–72. 27. Carmona F, Martínez-Zamora A, González X, Ginés A, Buñesch L, Balasch J. Does the learning curve of conservative laparoscopic surgery in women with rectovaginal endometriosis impair the recurrence rate? Fertil Steril 2009;92:868–75. 28. Taylor E, Williams C. Surgical treatment of endometriosis: location and patterns of disease at reoperation. Fertil Steril 2010;93:57–61. 29. Vercellini P, Aimi G, Panazza S, Vicentini S, Pisacreta A, Crosignani PG. Deep endometriosis conundrum: evidence in favor of a peritoneal origin. Fertil Steril 2000;73:1043–6. 30. Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990;1:43–6. 31. Bazot M, Bornier C, Dubernard G, Roseau G, Cortez A, Daraï E. Accuracy of magnetic resonance imaging and rectal endoscopic sonography for the prediction of location of deep pelvic endometriosis. Hum Reprod 2007;22:1457–63. 32. Bazot M, Darai E, Hourani R, Thomassin I, Cortez A, Uzan S, et al. Deep pelvic endometriosis: MR imaging for diagnosis and prediction of extension of disease. Radiology 2004;232: 379–89. 33. Piketty M, Chopin N, Dousset B, Millischer-Bellaische A-E, Roseau G, Leconte M, et al. Preoperative work-up for patients with deeply infiltrating endometriosis: transvaginal ultrasonography must definitely be the first-line imaging examination. Hum Reprod 2009;24:602–7.
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