Predictive risk factors for occurrence of tubo-ovarian abscess in patients with ovarian endometriosis: a prospective comparative study

Objective. To assess demographical and clinical criteria of patients with tu- bo-ovarian abscesses (TOAs) to evaluate predictive risk factors of occurrence of ovarian endometriosis-tubo-ovarian abscess (OE-TOA). Patients and Methods. In the current case control comparative study, 200 patients with OE were included and divided into the first group (the case) (composed of 80 patients with OE-TOA) and the second group (the control) (composed of 120 patients with OE but no TOA). Then we compared between both groups regarding all parameters. Results. There is statistically significant relation between occurrence of com- bined OE and TOA and spontaneous rupture of ovarian cyst (p = 0.026), his- tory of PID (p = 0.26) and presence of DM (p = 0.32). Spontaneous rupture of ovarian cyst and history of PID are significantly associated with combined OE and TOA. Lower genital tract infections were diagnosed in 8 (66.7%) of patients in the first group (OE-TOAs) and were diagnosed in only 4 (33.3%) patients with OE without TOAs (p = 0.042). History of spontaneous rupture of OE cyst and PID independently increased risk of TOA+ OE by 2.819 and 2.547 folds, respectively. Conclusions. We found that predictive risk factors of OE-TOA were rupture of OE cysts spontaneously in addition to lower genital tract infections, low immunity and neglected pelvic inflammatory diseases. Key words Tubo-ovarian abscess; ovarian endometriosis; risk factors. 197 Tubo‑ovarian abscess in patients with ovarian endometrios Ahmed Mahmoud Abdou, Ahmed M. Fahmy, Ola A. Harb, Abdel‑Razik El‑Sayed Abdel‑Razik

Pelvic inflammatory diseases (PIDs) are group of infections of the uterus, fallopian tubes and the ovaries [1]. PIDs clinical importance was studied due to their sequels that include infertility, persistent pelvic pain and ectopic pregnancy. Additionally, inade- quate treatment of PIDs might be complicated by pyosalpinx and tubo-ovarian abscesses (TOAs) which are severe complications that were reported in 15-34% of patients with PIDs [2, 3]. It was previ- ously hypothesized that PID and TOA have more liability to occur in severe degrees in patients with endometriosis more than in those without endo- metriosis [4]. Pelvic peritoneal endometriosis is an important cause of marked pelvic pain [5]. Endometriosis is as a disabling condition which worsen social, sexuality and mental health that might be caused by acute immunological reactions within the microenvironment of endometriosis le- sions [6]. Smoking could increase endometriosis risk mainly in infertile nulliparae patients [7]. Moreover, when TOAs were associated with ovar- ian endometriosis (OE-TOA), it occurs in a severe and even life-threatening form [8]. Macrophages are classified into pro-inflammatory M1 and M2 which induce immunotolerance and angiogenesis. Both were significantly higher in en- dometriosis [9]. There are many reported risk factors for PIDs and TOAs as young age of the patient, uterine instru- mentation, sexually transmitted infections, multi- ple sexual partners, hysterosalpingography, and in vitro fertilization (IVF) [10, 11]. AntiMullerian hormone (AMH) levels have a significant accuracy in pregnancy prediction in patients with ovarian endometriosis [12]. The role of neurotrophins in eutopic endometrium from endometriosis-patients was investigated and no differences were found between patients with and without endometriosis with regards to the neurite outgrowth of sensory ganglia [13]. Pelvic nerve-sparing surgery is effec- tive in improving intestinal symptoms after per - forming radical surgery for endometriosis which needed segmental intestinal resection [14]. However, there is a need for more comprehensive studies that assessed the risk factors for OE-TOA [15]. The aims of the present study were to assess de- mographical and clinical criteria of patients with TOAs, to evaluate incidence of occurrence of TOAs in patients with ovarian endometriosis, to evalu- ate predictive risk factors of occurrence of OE-TOA and finally to correlate between TOAs patients with and without endometriosis to allow early di- agnosis, prevention, and adequate treatment.

The current prospective comparative study is per - formed in Gynecology and Obstetrics Department, Faculty of Medicine, Zagazig University after tak- ing an approval from the local ethical committee and written informed consents from all patients. We included all cases with clinical, radiological and pathological evidence of endometriosis with or without TOAs who were surgically operated by laparotomy or laparoscopy in the period from March 2016 till March 2021. Inclusion and exclusion criteria of the study The surgical indications for all patients were pres- ence of an adnexal mass (greater than 4 cm in size). Criteria of inclusion of patients in the first group (the case) were detected pus during surgery then pathological confirmation of the presence of OE- TOA by detecting endometrial glands/stroma or hemosiderin laden macrophages in the detected tubo-ovarian cyst, in addition to detection of heavy infiltrate of neutrophils in the capsule of the ovari- an cyst and the tube. Criteria of inclusion of patients in the second group (the control) were no detected pus during surgery and pathological confirmation of the presence of only OE cysts without the presence of TOAs. The exclusion criteria were malignant tumour of any pelvic organs, suppurative appendicitis with or without appendicular abscesses and patients with incomplete or with lost data. After application of inclusion criteria, 200 patients with OE were included and were divided into the first group (the case) (composed of 80 patients with OE-TOA) and the second group (the control) (com- posed of 120 patients with OE but no TOA). We collected all demographic and clinical data of all patients in addition to collection of possible pre- dictive risk factors for OE-TOA. The collected data includes age, marital status, parity, primary or sec- ondary infertility, past history of PID or ectopic preg- nancy and history of previous OE cysts removal. We collected data about any previous performed sur - gery within 15 days as appendectomy, caesarean de- Ital J Gynaecol Obstet 2023, 35, N.2 198 Tubo‑ovarian abscess in patients with ovarian endometrios livery or uterine cavity surgery within 15 days. We recorded the presence of lower genital tract infection or spontaneous rupture of OE cysts, dysmenorrhea, and any co-existent medical disease as diabetes mel- litus or hypertension in addition to monitoring lev- els of carbohydrate antigen 125 (CA125). We treated all patients with one of the following 2 antibiotic regimens according to Centers for Dis- ease Control (CDC) guidelines: 1) IV doxycycline 100 mg every 12 h, IV cefoxitin 2 g every 6 h 2) IV clindamycin 900 mg every 8 h and gentamycin 1.5 mg/kg [9]. In case of lack of clinical improvement of the pa- tient, in addition to failure of medical treatment re- sponse within 48-72 h surgery was performed. Then we divided all included patients into two groups according to clinical and pathologic find- ings: the first group includes patients with histo- pathologically confirmed OE-TOAs and those with only OE without TOAs then we compared between both groups regarding all parameters. Ethical approval to perform the manuscript was taken from local ethical committee of Faculty of medicine Zagazig University. This manuscript conforms the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network guidelines. Statistical analyses were performed with SPSS version 17 (SPSS Inc., Chicago, IL, USA). We used Kolmogorov-Smirnov and Shapiro-Wilk tests for assessment of normality of data. We detected mean ± standard deviation (SD) for evaluating normally distributed data. We used in- dependent samples t-test, Mann-Whitney U test and Kruskal-Wallis tests for comparing the groups according variables distribution. We used chi- squared test for comparing categorical variables. Binary regression analysis was used to measure odds of risk factor in producing TOAs. Statistical significance was set at p < 0.05 for all tests.

A total of 200 women were evaluated in this study. Among these women, 80 were diagnosed with OE- TOA and 120 patients were diagnosed with OE without TOAs. The collected demographic data of both groups were found and compared in Table 1. Patients age ranges from 19 to 59 years with mean age 41.4 years and mean BMI was 24.92 kg/m 2. About 77% were married, out of them, 19% had pre- vious CS and 34% of them were infertile. Forty per- cent of the studied patients had OE-TOA. Diabetes and hypertension occurred in 6% and 5% of patients Table 1. Baseline data of the studied patients. Parameter n = 200 Age Mean ± SD Range 41.4 ± 7.72 19-59 BMI Mean ± SD Range 24.92 ± 3.11 20-30 Gravity Median (IQR) Range Nulligravida 2 (1-3) 0-5 24 (12%) Parity Median (IQR) Range Nullipara 1 (1-2) 0-5 24 (12%) Marital status Unmarried Married 47 (23.5%) 153 (76.5%) Infertility Absent Present n = 153 (%) 101 (66%) 52 (34%) History of ovarian cyst removal Absent Present 175 (87.5%) 25 (12.5%) Previous appendectomy Absent Present 186 (93.0%) 14 (7.0%) Previous CS Absent Present n = 105 85 (81.0%) 20 (19.0%) History of uterine surgery within 15 days Absent Present 190 (95%) 10 (5%) History of IVF Absent Present 191 (95.5%) 9 (4.5%) History of PID Absent Present 185 (92.5%) 15 (7.5%) Spontaneous rupture of OE cyst Absent Present 187 (93.5%) 13 (6.5%) Menstrual irregularities Absent Present 185 (92.5%) 15 (7.5%) Lower UTI Absent Present 188 (94%) 12 (6%) DM Absent Present 188 (94%) 12 (6%) Hypertension Absent Present 190 (95%) 10 (5%) 199 Tubo‑ovarian abscess in patients with ovarian endometrios Ahmed Mahmoud Abdou, Ahmed M. Fahmy, Ola A. Harb, Abdel‑Razik El‑Sayed Abdel‑Razik respectively. Concerning past history, 7%, 5%, 4.5%, 7.5%, 6.5%, 7.5% and 6% had history of previous appendectomy, uterine surgery within previous 15 days, IVF, PID, spontaneous rupture of OE, men- strual irregularities, and lower UTI (Table 2). There is statistically non-significant relation be- tween combined OE and TOA and either age of patients, BMI, gravity, parity, marital status, ec- topic pregnancy, surgical history, past history of removal of OE cysts, previous appendectomy, previous caesarean delivery or previous uterine cavity surgery. There is statistically significant relation between occurrence of combined OE and TOA and spon- taneous rupture of ovarian cyst (p = 0.26), history of PID (p = 0.26) and presence of DM (p = 0.32). Spontaneous rupture of ovarian cyst and history of PID are significantly associated with combined OE and TOA. There is statistically non-significant relation be- tween combined OE and TOA and either infertility, previous CS, menstrual irregularities, hypertension, history of ovarian cyst removal, previous appendec- tomy, history of uterine surgery (Table 3). The number of patients in the first group (OE- TOAs) using IUDs was more than that in the oth- er group (OE) only without TOAs (p = 0.042). Lower genital tract infections were diagnosed in 8 (66.7%) of patients in the first group (OE-TOAs) and were diagnosed in only 4 (33.3%) patients with OE without TOAs (p = 0.042). In multivariate analysis we showed that the most significant predictive risk factors for OE-TOAs are infections in the lower genital tract, OE cysts spon- taneous rupture and concomitant DM. Treatment options include hysterectomy in addi- tion to adnexectomy through laparotomy was per- formed for all post-menopausal patients and for some patients older than 40 years. Adnexectomy without total hysterectomy or ovarian cystectomy was performed in the remaining patients (68.6%) through laparoscopy (17.8%) or laparotomy (0.8%). Binary logistic regression analysis of factors associ- ated with combined OE+TAH among the studied patients (Table 4). History of spontaneous rupture of OE cyst and PID independently increased risk of TAH+ OE by 2.819 and 2.547 folds, respectively

OE is a relatively common gynaecological disor - der, but OE complicated by formation of secondary TOAs is relatively uncommon pathological finding that was reported to range from 2.15% in 1981 to 2.3% in 1997 [17, 18]. Of the 5,595 patients with OE in this study, 44 (0.79%) were diagnosed with OE- TOA. The incidence in Gao et al. [2] was markedly lower than that was reported in previous studies. Despite rarity of such disorder, it is considered a serious and even fatal disease sometimes fatal [1]. With advancement in using broad-spectrum antibi- otics therapy, TOAs incidence and fatality decreased but about 12.5-35% of females complained of PID were still in a need for surgical intervention [19]. Table 2. Relation between occurrence of combined OE and TOA and demographic data. Parameter Total n = 200 Group Test OE+non-TOA OE+TOA t p n = 120 (%) n = 80 (%) Age Mean ± SD Range 41.4 ± 7.72 19-59 40.34 ± 7.38 40-59 42.24 ± 8.11 19-43 -1.117 0.089 BMI Mean ± SD Range 24.91 ± 3.11 20-30 24.92 ± 3.14 20-30 24.91 ± 3.08 20-30 0.009 0.993 Gravity Median (IQR) Range 2 (1-3) 0-5 2 (1-3) 0-5 2 (1-3) 0-5 -0.109¥ 0.913 Parity Median (IQR) Range 1 (1-2) 0-5 1 (1-2) 0-5 1 (1-2) 0-5 -0.093¥ 0.926 Marital status Unmarried Married 47 (23.5%) 153 (76.5%) 32 (68.1%) 88 (57.5%) 15 (31.9%) 65 (42.5%) 1.673∞ 0.196 ¥Mann Whitney test; t: independent ample t-test; ∞ chi square test. Ital J Gynaecol Obstet 2023, 35, N.2 200 Tubo‑ovarian abscess in patients with ovarian endometrios It was found that patients with OE are more sus- ceptible to TOA [18]. According to recent reports, endometriosis was found to be a risk factor for TOAs occurrences [20, 21]. It was hypothesized that the initiating factor in TOA formation is invasion of the epithelium of fallopian tube by an organism that damaged the tissues causing necrosis thus abscess formation. There are several incriminated risk factors for TOAs other than OE as the sexual habits, old age and lower immunity [20, 21]. Mechanisms of occurrence of TOAs due to OE are: 1) OE is considered an immunodeficiency condi- tion which impairs the ability of the immune sys- tem to remove and overcome infections, thus leads to TOA; 2) the capsule of endometriotic ovarian Table 3. Relation between occurrence of combined OE and TOA and both medical and clinical characteristics. Parameter Total n = 200 Group Test OE+non-TOA OE+TOA t p n = 120 (%) n = 80 (%) Infertility Absent Present n = 153 (%) 101 (66%) 52 (34%) 56 (55.4%) 32 (61.5%) 45 (44.6%) 20 (38.5%) 0.522∞ 0.47 History of ovarian cyst removal Absent Present 175 (87.5%) 25 (12.5%) 109 (62.3%) 11 (44.0%) 66 (37.7%) 14 (56.0%) 3.048∞ 0.081 Previous appendicectomy Absent Present 186 (93.0%) 14 (7.0%) 112 (60.2%) 8 (57.1%) 74 (39.8%) 6 (42.9%) 0.051∞ 0.821 Previous CS Absent Present n = 105 85 (81.0%) 20 (19.0%) 51 (60.0%) 8 (40.0%) 32 (40.0%) 12 (60.0%) 2.631∞ 0.105 History of uterine surgery Absent Present 190 (95%) 10 (5%) 115 (60.5%) 5 (50.0%) 75 (39.5%) 5 (%50.0%) 0.439∞ 0.508 History of IVF Absent Present 191 (95.5%) 9 (4.5%) 117 (61.3%) 3 (33.3%) 74 (38.7%) 6 (66.7%) Fisher∞ 0.19 History of PID Absent Present 185 (92.5%) 15 (7.5%) 115 (62.2%) 5 (33.3%) 70 (37.8%) 10 (66.7%) 4.805∞ 0.028* Spontaneous rupture Absent Present 187 (93.5%) 13 (6.5%) 116 (62.0%) 4 (30.8%) 71 (38.0%) 9 (69.2%) 4.95∞ 0.026* Menstrual irregularities Absent Present 185 (92.5%) 15 (7.5%) 113 (61.1%) 7 (46.7%) 72 (38.9%) 8 (53.3%) 1.201∞ 0.273 Lower UTI Absent Present 188 (94%) 12 (6%) 116 (61.7%) 4 (33.3%) 72 (38.3%) 8 (66.7%) 3.783∞ 0.042 DM Absent Present 188 (94%) 12 (6%) 116 (61.7%) 4 (33.3%) 72 (38.3%) 8 (66.7%) 3.783∞ 0.032 Hypertension Absent Present 190 (95%) 10 (5%) 115 (70.5%) 5 (50%) 75 (39.5%) 5 (50%) 0.439∞ 0.508 ¥Mann Whitney test; t: independent ample t-test; ∞ chi square test; *p < 0.05 is statistically significant. Table 4. Binary logistic regression analysis of factors associated with combined OE+TAH among the studied patients. β Wald p AOR 95%CI Lower Upper Spontaneous rupture of cyst 1.037 2.567 0.109 2.819 0.793 10.018 Previous history of PID 0.935 2.47 0.116 2.547 0.794 8.175 AOR: adjusted odds ratio; CI: confidence interval. 201 Tubo‑ovarian abscess in patients with ovarian endometrios Ahmed Mahmoud Abdou, Ahmed M. Fahmy, Ola A. Harb, Abdel‑Razik El‑Sayed Abdel‑Razik cyst is thin which allow easy penetration of the bacteria; 3) blood content of the OE is a perfect me- dia for bacterial invasion and growth [22]; 4) the “bacterial contamination hypothesis” which states that occurrence of intrauterine bacterial coloniza- tion is higher in females with endometriosis [23]. Gao et al. [2] observed an increase in risk factors of OE-TOA after lower genital tract infection due to impairment in the cervical mucosal barrier during infection, so infection could easily spread to oth- er pelvic organs as tubes and ovaries which is a classic spread pattern [24]. It was found that the commonest incriminated organism for TOA was Neisseria gonorrhoeae in addition to Chlamydia tra- chomatis [25, 26]. Recent study demonstrated that Enterobacteriaceae and Streptococcus are the most frequently detected organisms in TOAs-OE [27]. We showed in the present study that detection rate of lower genital tract microbial infection in the lower genital tract was higher in the cases than in controls; additionally, the most detected organisms were Escherichia coli (50%), Mycoplasma genitalium (21.4%) and Gardnerella vaginalis (21.4%). These re- sults were in line with results of Gao et al. [2], con- firming the need to a prompt evaluation, diagnosis and treatment of these infections with suitable an- tibiotics before occurrence of ascending infections. We showed that rupture of endometriotic ovarian cyst was incriminated in increasing risks of OE- TOA and incidence of TOAs was more common in females with ruptured endometriotic cysts that females without rupture which was similar to

of Gao et al. [2], but the exact mechanism was not clarified yet. Possible explanations were previously demon- strated, as that the wall of the endometriotic cyst could easily rupture due bleeding inside it during menstruation, which increased intra-cystic pres- sure [28]. Additionally, after rupture of the cyst, pouring chocolate like material inside the abdom- inal cavity lead to peritonitis and abscess later on, moreover, cystic blood content is a suitable medi- um for flourishing bacterial infections [29]. If there was prompt initiation of treatment this will progress to more severe infections and TOAs. Once clinical diagnosis of OE-TOA is established early surgical intervention by drainage in addition to intravenous antibiotics is needed [30]. TOAs were found to be a rare disease in postmeno- pausal females in comparison with females in the reproductive period [2]. It was previously found that incidence of TOAs in postmenopausal females ranged from 12% and 18% by researchers previ- ously and was similar to our study (17.8%) [30, 31]. We showed that roles of endometriosis in causing TOAs were not only restricted to females in the re- productive period, but were found in post-meno- pausal females. Similarly results of Gao et al. [2], which could be explained by considering that en- dometriosis is a disease of dysregulation of both the endocrine and immune systems [32, 33]. Points of strengths of the study In the present prospective study, we highlighted the fact that suspecting TOAs showed be done in any case of OE which allowed early and better management for detected cases.

of the study include inclusion of a rel- atively few patient number due to performing the study in a single centre.

In the present study we showed an association between OE and TOAs in both females in the re- productive period and post-menopausal females, and we found that predictive risk factors of OE- TOA were rupture of ovarian endometriotic cysts spontaneously, in addition to lower genital tract infections, low immunity and neglected pelvic in- flammatory diseases. We recommend giving prophylactic broad spec- trum antibiotics to high risk and suspected pa- tients to decrease rate of occurrence and complica- tions of OE-TOA and improve patients prognosis. Additionally, we advise performing dramatic ap- propriate surgical drainage of diagnosed abscess. COMPLIANCE WITH ETHICAL STANDARDS Authors contribution A.M.A.: Conceptualization, data curation. A.M.F.: Project administration, resources, software, super- vision. O.H.: Validation, visualization, writing – original draft, writing – review & editing. A.E.A.: Formal analysis, investigation, methodology, con- ceptualization, data curation, funding acquisition, project administration, resources, software, super- vision, validation, visualization, writing – original draft, writing – review & editing. Ital J Gynaecol Obstet 2023, 35, N.2 202 Tubo‑ovarian abscess in patients with ovarian endometrios Funding None. Study registration Zag 101998. Disclosure of interests the authors declare that they have no conflict of in- terests. Ethical approval It was obtained from local ethical committee of Faculty of Medicine Zagazig University. Informed consent A written informed consent was obtained from all participants in the study. Data sharing Data are available under reasonable request to the corresponding author.

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