AOGS ORIGINAL RESEARCH ARTICLE Endometriosis and uterine malformations: infertility may increase severity of endometriosis JEREMY BOUJENAH 1,2, ELEONORA SALAKOS 1,M ELODIE PINTO 1, JOANNA SHORE 1, CHRISTOPHE SIFER 1,2, CHRISTOPHE PONCELET 1,2 & ALEXANDRE BRICOU 1 1 Department of Obstetrics, Gynecology and Reproductive Medecine, University Hospitals Paris Seine-Saint-Denis, Public Assistance Hospitals Paris, CHU Jean Verdier, Bondy, and 2 University Paris 13, Sorbonne Paris City, UFR SMBH, Bobigny, France Key words Endometriosis, uterine malformation, infertility, severity Correspondence Jeremy Boujenah, CHU Jean Verdier, Bondy Hospital, Avenue du 14 juillet, 93140 Bondy, France. E-mail: jeremy.boujenah@gmail.com Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Boujenah J, Salakos E, Pinto M, Shore J, Sifer C, Poncelet C, et al. Endometriosis and uterine malformations: infertility may increase severity of endometriosis. Acta Obstet Gynecol Scand 2017; 96:702 706. Received: 6 July 2016 Accepted: 9 October 2016 DOI: 10.1111/aogs.13040 Abstract Introduction. The aim of our study was to compare the stage and severity of endometriosis in fertile and infertile women with congenital uterine malformations. Material and methods. We performed an observational study from September 2007 to December 2015 in a tertiary care university hospital and assisted reproductive technology center. A total of 52 patients with surgically proven uterine malformations were included. We compared 41 infertile patients with uterine malformations with 11 fertile patients with uterine malformation. The main outcome was the stage, score and type of endometriosis in regard to infertility and class of uterine malformation. Results. The rate of endometriosis did not differ between the two groups (43.9 vs. 36.4%). The mean revised American Fertility Society score was higher in infertile patients with uterine malformations (19.02 vs. 6, p < 0.05). No significant difference was found in the rate of superficial peritoneal endometriosis (43.9 vs. 37.5%). Endometrioma and deep infiltrating endometriosis were associated with uterine malformations in infertile women, respectively 14.6 and 0%. No difference in the characteristics of endometriosis was found regarding the class of malformation. Conclusions. The association of uterine malformations and infertility may increase the severity of endometriosis and raise the issue of their diagnosis and management. Abbreviations: DIE, deep infiltrating endometriosis; ESGE, European Society for Gynaecological Endoscopy; ESHRE, European Society of Human Reproduction and Embryology; MRI, magnetic resonance imaging; PMSI, Medicalization of Information Systems Program (Programme de medicalisation des systemes d information). Introduction Endometriosis and congenital uterine malformation are often diagnosed while exploring infertility. Endometriosis can be found in 35% of women experiencing both pain and infertility (1). Uterine malformations can be found in 4% of infertile women and 15% of those who have undergone recurrent abortions (2). According to Sampson s theory (3), pelvic distortion and uterine malformations may favor the development of endometriosis. This hypothesis has been supported by both an observational study using laparoscopy to diagnose endometriosis in patients with M ullerian malformations (4,5), and by the characteristics of adolescence Key Message Endometriosis should be considered in infertile women with uterine malformations. 702
J. Boujenah et al. Endometriosis and uterine malformations endometriosis (6). Supporting the retrograde menstruation theory, obstructive M ullerian anomalies may be more closely associated with endometriosis compared with non-obstructive anomalies (5,7,8). However, endometriosis has been reported with all three main types of genitourinary malformations (uterine, cervical and vaginal anomalies) (9 11). Recently, Song et al. demonstrated that women with cervical atresia had an increased frequency of endometriosis (12). Large amounts of retrograde menstruations may also increase the severity of endometriosis related to uterine malformation. However, this hypothesis has not been studied. Hence, when uterine malformations are diagnosed in infertile patients, the role of possible endometriosis in the pathogenesis of infertility remains a matter of debate. The aim of our study was to compare the stage and severity of endometriosis in fertile and infertile women with congenital uterine malformations. Material and methods This retrospective, observational study was conducted in the gynecology-obstetrics and assisted reproductive technology (ART) department of a tertiary care university hospital. The study was approved by the Institutional Review Board of our university according to the PMSI (national Medicalization of Information Systems Program) database, which allows retrospective and prospective studies. All women booked to deliver or for surgery in our University Hospital are informed that data are routinely entered at birth into an electronic record-keeping system for the PMSI database, and that indicators of perinatal health are analyzed. Informed consent was obtained from each woman before beginning surgery. Data were routinely and prospectively collected for all women who underwent surgery in our university center and then reviewed by a data management professional. From September 2007 to December 2015, we evaluated all consecutive infertile and fertile patients who were treated for infertility or adverse obstetrical outcome suggesting uterine malformations and who underwent hysteroscopic and laparoscopic evaluations. Data on historic, physical examination, history of infertility, surgery, postoperative follow up and subsequent fertility were collected prospectively. To assess the correct morphology of the uterus, pelvic ultrasound, diagnostic hysteroscopy, and hysterosalpingography were systematically performed before surgery. Additional modern imaging technology was used if necessary: magnetic resonance imaging (MRI) when deep infiltrating endometriosis (DIE) or adenomyosis was suspected, and 3D-hysterosonography. When hemi-uterus was suspected, MRI was performed to differentiate those with and without a rudimentary cavity before surgery. When differentiation was impossible using MRI, hysterosonography was performed before surgery. Kidney and urinary tract ultrasound was performed for patients with hemi-uterus, bicorporeal uterus and unclassified uterine malformations. Laparoscopy was performed to confirm the morphology of the uterus, to exclude other possible causes of infertility (when tubal or pelvic peritoneal factors were suspected or when infertility was unexplained) and to treat endometriosis or to remove a rudimentary cavity. Patients with anovulation or other uterine anomalies were excluded (myoma, adenomyosis). Uterine malformations were classified in accordance with the new European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) consensus (13). The revised American Society for Reproductive Medicine classification and revised American Fertility Society Score were used to describe the stage and severity of endometriosis (14). As the ESHRE/ESGE classification system was only published in 2013, we reevaluated the uterine malformation retrospectively according to the imaging technique performed, the operative and imaging report and the previous established diagnosis. Two groups of women with uterine malformations were included. Group 1 consisted of infertile women with uterine malformations. These women were considered infertile when no previous spontaneous pregnancy was achieved for >18 months. Prior to surgery (operative hysteroscopy and laparoscopy), a complete evaluation including patient history and physical examination, partner semen analysis (15), hormonal profile, tubal assessment by hysterosalpingography was performed to rule out other causes of infertility. Endometrioma and DIE were diagnosed before the surgery in all cases with ultrasound and MRI. A total of 41 women were included. Group 2 consisted of fertile patients with uterine malformations. Women with a history of obstetrical adverse outcome (recurrent miscarriage defined by three or more consecutive pregnancy losses, malposition of the fetus defined by breech or transversal presentation, or preterm delivery defined as before 37 weeks of pregnancy) were considered fertile. Each patient had confirmed uterine malformation with pelvic ultrasound and diagnostic hysteroscopy after the obstetrical outcome. MRI was performed to diagnose the presence (class U4a) or absence (class U4b) of a rudimentary cavity. A total of 11 fertile women with uterine malformation were included. Statistical analyses Statistical analysis and figures were made using STATA statistical software version 11.0 (StatCorp, College Station, 703
Endometriosis and uterine malformations J. Boujenah et al. TX, USA). Descriptive data analysis was performed with the use of a non-parametric test: the Mann Whitney test and Wilcoxon test for continuous variables when comparing two independent variables. The chi-square test or Fisher exact test was used for qualitative variables when n < 5, and the McNemar test was used for paired data. Results Between September 2007 and December 2015, we recruited 52 patients with uterine malformations and explored by laparoscopy. The mean age of our cohort was 34 years and 1 month. The overall prevalence of endometriosis in our uterine malformation cohort was 50%. In the population, 41 women (78.8%) were infertile and 11 (21.2%) fertile. No difference was found in mean age or type of uterine malformations (Table 1). The mean revised American Society for Reproductive Medicine score was higher in infertile patients than in fertile patients with uterine malformations (19.1 vs. 6, p < 0.05), whereas the median did not differ. Minimal and mild endometriosis (stage I II) did not differ between the two groups. However, moderate and severe endometriosis (stage III IV) was more frequent in infertile than fertile women (17.5 vs. 0%). The rate of superficial peritoneal lesions was similar in the two groups. We did not observe a difference in the rate of superficial lesions. However, endometrioma (mean size 3.1 cm, systematically on the left side) and DIE was found only in infertile women with uterine malformations. Among women with septate uterus, 25 had partial septate uterus and 12 complete septate uterus (according to Table 1. Demographic and endometriosis characteristics according to fertility status. Uterine malformation with infertility n = 41 Uterine malformation without infertlity n = 11 Median age (range) 30 (21 41) 33 (20 41) NS Septate uterus 30 (73.17%) 7 (63.6%) NS Bicornuate uterus 7 (17.08%) 4 (36.4%) NS Endometriosis 18 (43.9%) 3 (27.3%) NS Median rafs score (range) 7 (4 120) 3 (2 10) NS Superficial peritoneal 18 (43.9%) 3 (37.5%) NS lesions Endometrioma 6 (14.6%) 0 NA Deep infiltrating endometriosis (uterosacral, torus, digestive, rectovaginal, bladder) 6 (14.6%) 0 NA rafs, revised American Fertility Society. Table 2. Characteristics of endometriosis according to the type of uterine malformation. ESHRE/ESGE consensus). Among patients with bicorporeal uterus (class U3), three women had a complete bicorporeal uterus and seven had partial bicorporeal uterus. Two women had a double cervix. Among women with hemi uterus (9.6% of the population, class U4) three had a rudimentary cavity. The three women with a rudimentary cavity had a functional cavity according to the ESHRE/ESGE consensus with hemato cavity for one of them. Two women with bicorporeal uterus had unilateral renal agenesis. According to the class of uterine anomaly (37 women with U3 septate uterus vs. 15 women with U4/U5 hemi uterus and bicorporeal uterus), the prevalence of endometriosis, its severity and rate of endometrioma and DIE were not different (Table 2). Whatever the fertility status, endometriosis related to uterine malformations was more frequent in women without a previous pregnancy (miscarriage, ectopic pregnancy, preterm or term delivery) (65.4 vs. 34.6%, p < 0.05). No in utero exposure to diethylstilbestrol was reported in the two groups of patients with uterine malformation. Discussion Septate uterus n = 37 Unicornuate and bicorporeal uterus n = 15 Infertility 30 (81%) 11 (68.7%) NS Endometriosis 20 (54%) 6 (37.5%) NS Endometriosis and infertility 16 (43.2%) 5 (31.2%) NS Median rafs score (range) 9 (2 124) 15 (2 120) NS Superficial peritoneal lesions 20 (55.8%) 6 (37.5%) NS Endometrioma 3 (11.7%) 3 (18.75%) NS Deep infiltrating endometriosis (uterosacral, torus, digestive, recto-vaginal, bladder) 3 (5.9%) 3 (18.75%) NS NS, not significant; rafs, revised American Fertility Society. Our results suggest a higher incidence of moderate and severe endometriosis (endometrioma and DIE) in infertile women with uterine malformations. We observed a higher rate of endometriosis in women with uterine malformations and without previous pregnancy. Several studies previously demonstrated the association between obstructive M ullerian anomalies and endometriosis and denied a link between non-obstructive malformation and endometriosis (4,5,8). These observations supported the theory of retrograde menstruation (18). However, no comparison was made with a fertile group, with or without uterine malformation (8). 704
J. Boujenah et al. Endometriosis and uterine malformations Other authors found an association between nonobstructive M ullerian anomalies and endometriosis (12,13,17,20), but most of these published studies involved septate uterus. Moreover, none of these studies reported the severity of the disease or distinguished fertile from infertile patients (4,5,8,12). Other authors reported that uterine malformation may contribute to the severity of endometriosis (9,10). Recently, La Monica et al. (18) reported a more advanced stage in septate uterus. However, heterogeneity in the groups (pain, infertility, abnormal bleeding), and the lack of data on obstetrical history and overall prevalence of endometriosis, limited the results of that study (18). No difference was found regarding the class of malformation; other studies reported a higher rate of endometriosis among unicornuate uterus (8) or among bicornuate or didelphic uteri with renal agenesis (20). Our different results might be explained by the low numbers in each sub-group. Our study has some limitations. We did not compare the rate and type of endometriosis with a group of patients without uterine malformations. Other limitations are the retrospective design and the few number of included women. The respective role of uterine malformations and endometriosis in the pathophysiology of infertility remains unclear (19). Whereas uterine malformation may lead to an increased risk of miscarriage, endometriosis could be an incidental finding without influencing fertility outcome (21). According to the literature and our results, infertility may increase the severity of endometriosis related to uterine malformations, but the reverse has not been proven. In our study, we considered the three types of endometriotic lesions. The pathogenesis of these three types seems to support a different explanation. In the absence of obstruction, uterine dysperistalsis has been suggested to explain endometriosis in septate uterus (22). The severity of endometriosis found in uterine anomalies evokes the theories of coelomic metaplasia or M ullerian embryonic rest, as well as genomic factors (16). These theories are often suggested for the adolescent form of endometriosis and could provide another explanation for its association with uterine malformations (23,24). Our study, however, has practical implications. Endometriosis should be considered first in infertile women with uterine malformations and second in adolescent women with uterine malformations accompanied by clinical symptoms (dysmenorrhea, dyspareunia). Thus, the imaging technology performed to assess the type of uterine malformations should also focus on possible endometriosis. Therefore, the early diagnosis by imaging of endometriosis in infertile patients with uterine anomalies should be attempted with the help of imaging exams. The decision to perform laparoscopy as well as provide Assisted Reproductive Technology in these situations needs to be evaluated by further studies in infertility management. Conclusion Our results suggest that the association of uterine malformations and infertility increases the risk of severe endometriosis. Therefore, the diagnosis of endometriosis should be considered in the etiology of infertile uterine malformations. Funding The study was not financially supported by any foundation or organization. References 1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235 58. 2. Saravelos SH, Cocksedge KA, Li TC. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum Reprod Update. 2008;14:415 29. 3. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422 69. 4. Olive DL, Henderson DY. 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