Risk factors for intraoperative adhesion in ovarian endometriosis patients: A retrospective study

Endometriosis is a gynecological disease that affects more than 10% of women of reproductive age worldwide. [ 1 ] Functional endometrial glands and stroma grow outside the uterine cavity in patients with endometriosis, with the ovaries being the most common site. [ 2 ] The main pathological alterations are periodic bleeding of the ectopic endometrium and fibrosis of the surrounding tissue, which results in cyst formation and fibrous tissue proliferation or adhesion. [ 3 ] Endometriosis is considered one of the main causes of adhesions unrelated to a previous operation. [ 4 ] Adhesion formation is an excessive reparative response to peritoneal injury. Multiple systems are involved in this process, including the inflammatory, immune, and coagulation systems. [ 5 ] Severe adhesions caused by endometriosis may aggravate pelvic pain or lead to infertility. Furthermore, severe adhesions increase the difficulty of surgery, resulting in prolonged operation time, increased intraoperative bleeding, and increased complications, including injuries to the bladder, ureter, intestine, and blood vessels. [ 6 ] In addition, adhesions may affect the integrity of the surgical resection and increase the risk of postoperative recurrence. If the degree of pelvic adhesion can be effectively evaluated before surgery, surgeons could prepare more thoroughly and select a more appropriate operative approach: a better method, which is of considerable clinical value for improving surgical outcomes and reducing surgical complications. As current research on endometriosis advances, it is believed that the occurrence and development of endometriosis are closely associated with processes such as inflammation, immunity, and coagulation. [ 7 ] Several serum biomarkers, including routine blood counts, coagulation parameters, and tumor markers, have been individually investigated for their association with endometriosis. However, existing evidence remains fragmented and largely focuses on the diagnostic accuracy of the disease itself, rather than on predicting the severity of pelvic adhesions. [ 8 , 9 ] Consequently, a practical, noninvasive, multifactorial model for preoperatively stratifying adhesion severity in patients with ovarian endometriosis is lacking. To address this gap, the present study systematically evaluated the relationships between preoperative peripheral blood indices, including routine blood, coagulation, and tumor marker tests, and the severity of pelvic adhesions, as assessed using the modified American Fertility Society (mAFS) scoring system, in a relatively large cohort of patients with surgically confirmed ovarian endometriosis. This study aimed to provide a clinically accessible tool for preoperative adhesion evaluation and individualized surgical management.

Conceptualization: Ling Zhou, De-Zhao Chen, Pei-Fang Chen, Hui-Lan Wang, Zhi-Qun Zheng. Data curation: Ling Zhou, Tong-Fei Wang, Zhen-Zhen Lai. Formal analysis: Ling Zhou, Ting-Ting Jiang. Funding acquisition: Ling Zhou. Investigation: Xiu-Shan Feng. Validation: Zhi-Qun Zheng. Writing – original draft: Ling Zhou. Writing – review & editing: Tong-Fei Wang, Xiu-Shan Feng, Zhen-Zhen Lai, De-Zhao Chen, Hui-Lan Wang, Zhi-Qun Zheng.

This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Fujian Medical University Union Hospital (Ethical approval No: 2023KY026). Written informed consent was obtained from all the participants. This retrospective study included women who underwent surgery for pathologically confirmed ovarian endometriosis at Fujian Medical University Union Hospital, Fuzhou, China, between January 2018 and September 2024. Women were eligible for recruitment in this study if they met the following criteria: ovarian endometriosis confirmed by pathology, no previous history of abdominal surgery, complete clinical data and no signs of infection or rupture. The exclusion criteria were as follows: comorbid hematologic disorders or complications of blood system diseases and abnormal coagulation function, complications of other tumors affecting relevant tumor markers, preoperative use of anticoagulants, antiplatelets, or other drugs and history of treatment for endometriosis before surgery. All data were obtained from the information system of Fujian Medical University Union Hospital. Basic patient information was recorded, including body mass index (BMI), age, the presence of dysmenorrhea or chronic pelvic pain, and the cyst location and size of the ovarian endometriotic cysts. Two experienced gynecologists scored the endometriosis according to the revised staging system proposed by the American Society of Fertility Medicine. Scores of 1 to 5 were classified as stage I; 6 to 15, stage II; 16 to 40, stage III; and >40, stage IV. The surgeon evaluated the presence, extent, and tenacity of the adhesions at 15 anatomical sites: the anterior uterus, posterior uterus, anterior abdominal wall, anterior cul-de-sac, posterior cul-de-sac, right pelvic sidewall, right ovary, right tube, left pelvic sidewall, left ovary, left tube, medial leaf of the broad ligament, small bowel, large bowel, and omentum. Two experienced gynecologists independently scored adhesions without access to the patients’ preoperative blood biomarkers and clinical data, and discrepancies were resolved by consensus after joint review of the intraoperative records and operative videos. According to the mAFS scoring method for adhesions (Table 1 ), the patients were divided into a no or mild adhesion group (scores of 0–3) and a moderate to severe adhesion group (scores of 4–6). [ 10 ] Clinically, scores of 0 to 3 indicate sparse, filmy adhesions with low surgical difficulty, whereas scores of 4 to 6 reflect extensive dense adhesions associated with prolonged operation time, increased bleeding, and higher visceral injury risk. This binary grouping may facilitate identification of high-risk patients with complex pelvic conditions for preoperative risk prediction. Modified American Fertility Society Scoring Method for Adhesions. mAFS = modified American Fertility Society. Within one month before surgery, a gynecological ultrasound examination was performed to determine the location and size of the endometriotic cysts. Blood samples were collected from the cubital vein for basic blood tests (including tumor markers, coagulation indicators, and routine blood tests) within 2 weeks before surgery. Test results were obtained from the Clinical Laboratory Center of Fujian Medical University Union Hospital. Routine blood counts were measured using an automated 5-part differential hematology analyzer, and coagulation indices were measured using an automated coagulation analyzer. CA125, CA19-9, and human epididymis protein 4 (HE4) levels were measured by immunoassay. The neutrophil–lymphocyte ratio (NLR) was calculated as the absolute neutrophil count/absolute lymphocyte count. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY). Missing data in this study were assumed to be missing at random (MAR). Multiple imputation was performed to handle missing values, retain the full sample size, and reduce bias. Continuous data were tested for normality using the Shapiro–Wilk test. Normally distributed data are presented as means ± standard deviations and were compared using t tests; skewed data are presented as medians (25th, 75th percentiles) (M [P25, P75]) and were compared using the Mann–Whitney U test. Categorical data are presented as n (%) and were compared using chi-square tests. Statistically significant factors were included in the multivariate logistic regression analysis. Statistical significance was set at P  < .05. Post hoc statistical power analysis was conducted using G*Power 3.1 to verify the statistical efficacy of the present retrospective study.

In total, 314 patients with histologically confirmed endometriosis were included in this study. According to the mAFS scoring method, 128 patients were included in the no or mild adhesion group, whereas 186 patients were included in the moderate-to-severe adhesion group. Minor missing values were observed for 4 serum biomarkers: CA125 (missing rate = 1.0%), CA19-9 (4.1%), HE4 (4.1%), and DDI (7.0%). Multiple imputation was applied to the missing data, and 5 imputed datasets were generated. All variables intended for subsequent statistical analyses were incorporated into the imputation model, and the pooled results across all datasets were synthesized based on Rubin’s rules. Patient characteristics are shown in Table 2 . There were no significant differences in BMI, size, or pain symptoms between the no or mild adhesion group and the moderate-to-severe adhesion group ( P  > .05). The locations of the cysts differed significantly between the 2 groups ( P  = .003). Left-sided cysts were the most common finding in the no or mild adhesion group (51.6%), whereas right-sided cysts predominated in the moderate-to-severe adhesion group (37.6%). Left-sided lesions were significantly more frequent in the no or mild adhesion group than in the moderate-to-severe adhesion group (51.6% vs 35.5%). In the moderate-to-severe adhesion group, the proportion of bilateral lesions (26.9%) was significantly higher than that in the no or mild adhesion groups (13.3%). Characteristics between the no or mild adhesion group and the moderate to severe adhesion group. Compared with the no or mild adhesion group, P  < .05. BMI = body mass index, rAFS = revised American Fertility Society. Age was significantly lower in the no and mild adhesion group than in the moderate-to-severe adhesion group ( P  < .05). Considering the revised American Fertility Society stage, the no or mild adhesion group had the highest percentage of patients in stage III (86.7%), which was significantly higher than that of the moderate-to-severe adhesion group (36.0%). Whereas the proportion of stage IV patients in the moderate-to-severe adhesion group (63.4%) was significantly higher than that in the no or mild adhesion group (10.2%) ( P  < .05). The laboratory characteristics of patients in each group are shown in Table 3 . There were no significant differences in the white blood cell, neutrophil granulocyte count, leukomonocyte, mononuclear leucocyte, hemoglobin, blood platelet, HE4, prothrombin time, international normalized ratio activated partial thromboplastin time thrombin time (TT), or D-dimer between the 2 groups ( P  > .05). In contrast, the NLR, CA125, CA19-9 and fibrinogen (FIB) levels were significantly higher in the moderate-to-severe adhesion group than in the no or mild adhesion group (all P  < .05). Comparison of laboratory characteristics between the no or mild adhesion group and the moderate to severe adhesion group. APTT = activated partial thromboplastin time, FIB = fibrinogen, HE4 = human epididymis protein 4, INR = International normalized ratio, NLR = neutrophil–lymphocyte ratio, TT = thrombin time, WBC=white blood cell. Multicollinearity among all covariates was assessed using the variance inflation factor (VIF) via linear regression prior to multivariate logistic regression analysis (Table 4 ). All variables exhibited VIF values <10, indicating no substantial multicollinearity between the independent variables. Variance inflation factor values of variables. VIF = variance inflation factor. Statistically significant indicators in the univariate analysis (age, location, NLR, CA125, CA19-9, FIB) were included in the multiple logistic regression analysis, and the results are shown in Table 5 . The analysis suggested that location, age, and FIB level were independent risk factors for moderate-to-severe pelvic adhesions. The Hosmer-Lemeshow test yielded χ 2  = 5.834, P  = .666 (>.05), indicating adequate model fit. Multivariate logistic regression. CI = confidence interval, FIB = fibrinogen, NLR = neutrophil–lymphocyte ratio. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value for each continuous variable (Fig. 1 ). The area under the curve (AUC) was 0.634 (95% confidence interval (CI) 0.571–0.697) for age, 0.603 (95% CI, 0.540–0.666) for cyst location, and 0.569 (95% CI, 0.504–0.633) for FIB. The corresponding sensitivities and specificities were 53.8% and 70.3% for age (optimal cutoff, 35.5 years), 64.5% and 51.6% for cyst location, and 50.0% and 63.3% for FIB (optimal cutoff, 3.015 g/L). Overall discrimination was modest, with age performing best of the 3. ROC curves of location, age, and FIB. FIB = fibrinogen, ROC = receiver operating characteristic. Post hoc power analysis for the overall multivariate logistic regression model was performed using G*Power 3.1. With 6 predictors and a total sample size of 314, Nagelkerke’s pseudo- R 2 was 0.1798(calculated using SPSS), corresponding to Cohen’s f 2 of 0.2191. The overall model achieved a statistical power >0.99 at α = 0.05, indicating adequate sample size for risk factor screening. post hoc power analyses.

Endometriosis is a prevalent gynecological disorder among women of reproductive age and is frequently complicated by the formation of adhesions around ectopic lesions. In this study, we enrolled patients with ovarian endometriosis to analyze routine preoperative laboratory and clinical parameters, identify independent risk factors for moderate-to-severe pelvic adhesions, and evaluate their predictive performance, with the aim of providing evidence for establishing a noninvasive and convenient preoperative assessment system for pelvic adhesion severity. Univariate analyses revealed that patients in the moderate-to-severe adhesion group were older, had a higher proportion of bilateral ovarian endometriomas, and exhibited significantly higher serum levels of NLR, CA125, CA19-9, and plasma FIB than those in the no or mild adhesion group (all P  < .05). No significant intergroup differences were observed in BMI, maximum cyst diameter, presence of pelvic pain, D-dimer levels, or other routine hematological and coagulation indicators. Mechanistically, older patients typically have a longer disease course than younger patients. Recurrent cyclic bleeding of the ectopic endometrium persistently drives chronic pelvic inflammation, peritoneal injury, and progressive fibrosis, ultimately leading to extensive pelvic adhesions. Bilateral ovarian lesions expand the scope of inflammatory stimulation and involve the entire pelvic peritoneum, predisposing patients to the formation of dense adhesions between the uterus, ovaries, fallopian tubes, and pelvic sidewall. Because neither cyst size nor pain symptoms discriminated between adhesion grades, clinical assessment based on these features alone appears insufficient to gauge the extent of pelvic adhesions. In the present study, serum CA125 and CA19-9 levels were markedly elevated in patients with moderate-to-severe adhesions, a finding that may reflect chronic aseptic pelvic inflammation driven by persistent bleeding from ectopic lesions. Both tumor markers are synthesized and secreted by activated peritoneal mesothelial cells and ectopic endometrial glandular epithelial cells. Repeated microruptures of endometriomas cause the leakage of highly concentrated CA125 and CA19-9 into the pelvic cavity, and proinflammatory cytokines further upregulate their gene expression. [ 11 ] CA125 is a well-recognized serological biomarker of endometriosis. However, elevated CA125 levels have been detected in various other conditions, including ovarian, lung, breast, and gastrointestinal malignancies. Its diagnostic performance for endometriosis varies considerably, and most patients with early stage disease have levels within the normal range, [ 12 ] resulting in relatively low diagnostic specificity and sensitivity. Despite these limitations, accumulating evidence has confirmed that CA125 levels are highly correlated with the severity of endometriosis-related pelvic adhesions, which is consistent with our findings. [ 13 ] Chronic inflammation is a core pathological process underlying the initiation and progression of endometriosis and contributes to pain, perilesional tissue remodeling, fibrosis, pelvic adhesions, and infertility. Additionally, recurrent bleeding coupled with the continuous clearance of hemoglobin by macrophages further amplifies inflammatory responses and promotes adhesion formation. [ 14 ] Following the implantation of endometrial tissue into the peritoneum, inflammatory cells such as neutrophils and macrophages are recruited, which in turn induce the secretion of inflammatory and angiogenic factors, including tumor necrosis factor, interleukin-1, interleukin-6 and vascular endothelial growth factor. [ 15 ] Various inflammatory cells collectively participate in the survival, proliferation, and adhesion of ectopic endometrial tissue. [ 16 ] The wider the extent of the pelvic adhesions, the more intense the cycle of peritoneal inflammatory injury and repair, leading to elevated levels of peripheral blood biomarkers. As a systemic marker of inflammation, the NLR rose in parallel with adhesion severity in our cohort. Several studies have demonstrated that the NLR reliably reflects systemic inflammatory and immune status and correlates well with serum CA125 levels in the diagnosis of stage III–IV endometriosis. Furthermore, the NLR maintains diagnostic value for stage III–IV endometriosis, even in patients with negative CA125 results, [ 17 ] indirectly indicating a state of systemic low-grade inflammation accompanying extensive pelvic fibrosis. Variables with statistical significance in the univariate analysis were entered into a multivariate binary logistic regression model to adjust for confounding factors. These results confirm that advanced age, bilateral ovarian cysts, and elevated plasma FIB levels are independent risk factors for moderate-to-severe pelvic adhesions in patients with endometriosis. Each 1-year increase in age was associated with a 7.0% higher risk of moderate-to-severe adhesions (odds ratio [OR] = 1.070, 95% (CI): 1.036–1.106, P  < .001). Compared to unilateral ovarian cysts, bilateral lesions increased the adhesion risk by 73.0% (OR = 1.730, 95% CI: 1.243–2.408, P  = .001). As a key coagulation protein regulating pelvic fibrosis, each 1 g/L elevation in FIB level was associated with a 55.7% increase in adhesion risk (OR = 1.557, 95% CI: 1.010–2.402, P  = .045). Previous evidence indicates that the cyclic bleeding of ectopic endometrial tissue in endometriosis activates the coagulation system. Activated platelets aggregate around endometriotic lesions, and FB is converted to fibrin, which stabilizes the resulting clot. [ 18 ] Chronic pelvic inflammation activates the coagulation cascade and stimulates hepatic FIB synthesis. Abundant fibrin deposits on visceral surfaces cannot be promptly degraded by the fibrinolytic system and are subsequently organized into adhesive bands. Established adhesions sustain the pelvic inflammatory microenvironment and further upregulate FIB levels, forming a vicious cycle of inflammation, coagulation dysregulation, and pelvic fibrosis. [ 19 ] We evaluated the predictive value of age, cyst laterality, and FIB level for moderate-to-severe pelvic adhesions using receiver operating characteristic curves. AUC values of the 3 indicators ranged from 0.569 to 0.634, all below 0.70, suggesting limited discriminative efficacy of any single marker for moderate-to-severe pelvic adhesions. Age yielded the highest AUC (0.634), with an optimal cutoff value of 35.5 years, corresponding to a sensitivity of 53.8% and specificity of 70.3%. FIB had an AUC of 0.569, with a sensitivity of only 50.0% at a cutoff value of 3.015 g/L. The AUC for cyst laterality was 0.603. These findings indicate that, although the above indicators show statistically significant associations with adhesion severity in both univariate and multivariate analyses, they are insufficient to serve as reliable standalone preoperative predictors of moderate-to-severe adhesions from a diagnostic test perspective. This may be explained by the complex pathogenesis of endometriosis-related pelvic adhesions, which is modulated by multiple factors. Age only indirectly reflects disease duration and the decline in tissue repair capacity but cannot quantify innate interindividual differences in fibrotic predisposition or the invasive potential determined by lesional heterogeneity. As a systemic coagulation parameter, FIB is influenced by various systemic factors, including hepatic synthetic function, systemic metabolic status, acute-phase response, and stress, and lacks tissue specificity to reflect local fibrin deposition and degradation in the pelvic microenvironment. Although bilateral ovarian endometriomas indicate a wider anatomical extent of peritoneal involvement, they cannot capture dynamic events, such as recent cyst rupture or chemical peritonitis induced by cyst fluid leakage. Collectively, these factors account for the limited efficacy of individual indicators and highlight the necessity of a combined multi-indicator assessment to improve preoperative prediction accuracy. Nevertheless, all 3 AUC values were significantly >0.5, indicating modest but real discriminative value with complementary strengths: age had the highest specificity (70.3%) and cyst laterality the highest sensitivity (64.5%), while FIB was the only marker directly reflecting the coagulation pathway implicated in fibrosis. From a clinical practice standpoint, these findings have dual implications for preoperative decision-making. On the 1 hand, AUC values below 0.7 indicate that no single indicator can be used for definitive diagnosis. On the other hand, despite their limited efficacy, these markers have clinical reference values. In settings where direct imaging assessment is unavailable or advanced imaging techniques are inaccessible, simple cutoffs such as age >35.5 years, bilateral cysts, and FIB >3.015 g/L can serve as early warning signals. They enable surgeons to anticipate surgical difficulties in advance, prepare blood products and antiadhesion materials, and allocate sufficient operative time. The advantages of low cost, easy accessibility, and good reproducibility make them suitable for preliminary risk stratification in primary care facilities and emergency scenarios. This study has several limitations. First, this was a single-center retrospective study, and all enrolled patients were surgical cases, most of whom had stage III–IV endometriosis; therefore, inherent selection and information biases are unavoidable. Second, this study analyzed the diagnostic efficacy of individual indicators separately and did not construct a multi-indicator combined prediction model. Further exploration integrating more biomarkers is warranted to optimize preoperative predictive performance. Third, limited by the single-center retrospective design and the incompatibility between multiple imputation and SPSS bootstrap functions, neither standardized internal bootstrap validation nor external validation was performed. The generalizability of our findings requires further verification in larger multicenter cohorts.

In conclusion, advanced age, bilateral ovarian cysts, and elevated preoperative FIB levels were independent risk factors for moderate-to-severe pelvic adhesions in patients with ovarian endometriosis. For patients presenting with these characteristics, more thorough preoperative planning may help anticipate the surgical challenges posed by complex adhesions, and individualized antiadhesion strategies should be considered. Future research should focus on establishing a multi-factor combined prediction model and elucidating the specific molecular mechanisms of FIB regulatory pathways in endometriosis-related adhesion.