Sex Differences in Non-strangulated Postoperative Adhesive Small Bowel Obstruction: A Retrospective Cohort Study

Background: Adhesive small bowel obstruction (ASBO) is one of the major causes of postoperative morbidity. Conservative treatment is generally applied to non-strangulated ASBO. Several factors have been reported to affect the response to conservative treatment in patients with ASBO. However, the association between sex differences and non-strangulated ASBO remains unclear. This study aimed to elucidate the effect of sex differences in non-strangulated postoperative ASBO. Methods: We divided 192 admissions of 99 patients with non-strangulated postoperative ASBO into two groups: the male group (n = 137) and female group (n = 55). Clinical features and prognosis were compared between the two groups. Results: Female patients had signicantly poorer performance status (p < 0.001) and lower proportions of esophageal/gastric malignancies (p = 0.002), colorectal malignancies (p = 0.034), and history of ASBO (p = 0.028) than male patients. More female patients failed conservative treatment (p = 0.036) than male patients. Hospital length of stay (LOS) was longer (p = 0.002) in the female group than in the male group. Multiple logistic regression analysis showed that female sex was associated with increased odds of requiring elective surgery (odds ratio 2.381, p = 0.040). The Cox proportional hazards regression model revealed that female sex was an independent predictor of hospital discharge (hazard ratio 0.651, p = 0.015). Conclusion: Female sex adversely affected the response to conservative treatment and LOS in patients with non-strangulated postoperative ASBO.


Background
Adhesive small bowel obstruction (ASBO) is one of the major causes of postoperative morbidity.
Regarding the treatment of ASBO, when computed tomography (CT) suggests strangulation, which indicates intestinal ischemia, including decreased bowel wall enhancement, mesenteric edema, and a closed loop sign, emergency surgery is recommended (1)(2)(3). Although most patients with ASBO without strangulation (non-strangulated ASBO) respond to gastrointestinal decompression (4), some of them fail and develop persistent bowel obstruction, resulting in prolonged hospital length of stay (LOS). Based on CT imaging ndings, we have previously reported that the feces sign (FS) in the transitional zone (TZ) is a good prognostic marker in non-strangulated postoperative ASBO, whereas male sex shows a tendency to be associated with an increased odds for hospital discharge (odds ratio 1.682, 95% con dence interval [CI] 0.972-2.911, p = 0.063) (5). In that study, we limited the study cohort to patients whose TZ was visible on CT.
Several diseases have been reported to be associated with sex differences. For example, women are associated with a better prognosis than men are in colorectal cancer (6,7). The incidence of gallstones was signi cantly higher in women than in men, and the sex differences decreased with increasing age (8). However, the relationship between ASBO and sex differences remains unclear. In this study, we aimed to evaluate the effect of sex differences in non-strangulated postoperative ASBO.

Ethics statements
This study was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and approved by the Ethical Committee of Shinshu University Hospital (approval number: 4864). Informed consent was obtained from each patient included in this study by using the opt-out method.
The opt-out method was approved by the Ethical Committee of Shinshu University Hospital.

Patients and study design
This retrospective cohort study aimed to evaluate the effect of sex differences in non-strangulated postoperative ASBO and included patients with postoperative ASBO who were admitted to Shinshu University Hospital between November 2007 and June 2020. ASBO was diagnosed based on clinical symptoms, including nausea, emesis, and abdominal pain as well as radiological imaging that demonstrated a dilated small intestine with a diameter > 2.5 cm. During that period, 130 patients (228 admissions) with postoperative ASBO were admitted to our department. We excluded 36 admissions of 36 patients who required emergency surgery due to intestinal ischemia caused by strangulation and con rmed by CT imaging. Our nal study group consisted of 192 admissions of 99 patients with nonstrangulated postoperative ASBO. They were divided into the following two groups: the male group (n = 137) and female group (n = 55) (Fig. 1).
We compared and examined the clinical backgrounds, ndings on admission, and prognosis between the two groups. With regard to the management of ASBO, intravenous uids were administered to all patients. Initially, we assessed the CT ndings of strangulation of the small intestine, which requires emergency surgery. When strangulation was excluded, the patients were judged to be candidates for conservative management to treat non-strangulated ASBO. Regarding general treatment strategies for non-strangulated ASBO, patients with active symptoms, such as abdominal pain and nausea, were treated with gastrointestinal decompression, including nasogastric tube placement, hyperbaric oxygen therapy, and long tube placement. Patients with improving symptoms on admission were initially managed with fasting in the rst 24-48 hours. When the obstruction persisted, the patients underwent gastrointestinal decompression. When their obstructions continued for more than 1 week or recurred after diet resumption, they were considered to have failed conservative treatment and underwent elective surgery.

Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences version 23.0 (IBM Corp., Armonk, NY, USA). Demographic data are presented with descriptive statistics. Non-parametric data are presented as medians with interquartile ranges. The Mann-Whitney test was used to compare non-parametric data. Comparisons between qualitative variables were conducted using the chi-square test. LOS was evaluated using the Kaplan-Meier estimator. Multiple logistic regression analysis (forward selection method using a likelihood ratio test) was conducted to identify the patient factors associated with failure of conservative treatment for ASBO using variables that reached p < 0.25 in univariate analysis. The results of multiple logistic regression analysis are described as odds ratios (ORs) with 95% con dence intervals (CIs). Cox proportional hazards regression model (forward selection method using the likelihood ratio test) was conducted to assess the effect of patient factors on LOS using variables that reached p < 0.25 in univariate analysis. The results of Cox proportional hazards regression analysis are described as hazard ratios (HRs) with 95% con dence intervals (CIs). All tests were two-tailed, and differences with a p value of < 0.05 were considered statistically signi cant.

Results
The baseline characteristics of all patients are shown in Table 1   Next, we examined the effect of sex differences on the requirement for elective surgery to treat nonstrangulated ASBO. As a result of multiple logistic regression analysis of the clinical background and ndings upon admission, female sex was associated with an increased odds for the requirement for elective surgery (OR 2.381, 95% CI 1.042-5.440, p = 0.040), whereas body mass index was associated with a decreased odds (OR 0.875, 95% CI 0.769-0.996, p = 0.043) ( Table 3). Asterisk indicates a statistical signi cance (p < 0.05). CI, con dence interval.
Finally, we assessed the effect of sex differences on LOS. The Kaplan-Meier estimator revealed that the female group had a signi cantly longer LOS than the male group (p = 0.002) (Fig. 2).

Discussion
In the present study, we found that female sex was associated with an increased odds of requiring elective surgery to treat non-strangulated postoperative ASBO and prolonged LOS.
We have previously reported that FS is associated with good prognosis in patients with non-strangulated postoperative ASBO, on the condition that the patients who required emergency surgery and whose TZ was invisible on CT were excluded (5). In line with our previous report, this study showed that FS and PS as well as sex differences were signi cantly associated with LOS. Several factors affect prognosis in patients with ASBO. For example, FS (9, 10), number of TZs (11), number of beak signs (12), anterior adhesion (13,14), and water-soluble contrast agent administration (13)(14)(15) have been reported to be associated with successful non-operative treatment in patients with ASBO. It has been reported that male sex was not associated with the need for operative exploration in univariate analysis (OR 0.61, 95% CI 0.28-1.35, p = 0.224) (10) and successful non-operative management in multivariate analysis (OR 1.60, 95% CI 0.90-3.10) (15). Even though these studies did not reach statistical signi cance, they showed that female sex was associated with poorer prognosis in ASBO than male sex. The cohort in this study did not include patients who underwent emergency surgery, resulting in only one patient presenting with a closed loop sign on CT on admission ( Table 2). This may explain why female sex has not been reported to inversely affect the prognosis of postoperative ASBO.
The main etiology of sex differences in several diseases is sex hormones, in particular, estrogen. It has been reported to be associated with increased risks of coronary heart disease, breast cancer, stroke, and pulmonary embolism, and conversely a decreased risk of colorectal cancer, endometrial cancer, and hip fracture (16). In the present study, female sex was associated with failure of conservative treatment and prolonged LOS, whereas primary diseases including uterine and ovarian malignancy did not affect failure of conservative treatment or prolonged LOS, according to the results of multiple logistic regression analysis of the requirement for elective surgery (Table 3) and Cox proportional hazard regression of hospital discharge (Table 4). This nding suggests that the cause of poor prognosis in the female group is derived from female intrinsic factors, such as physiological and anatomical differences. However, there have been no previous reports on the association of sex differences with response to the treatment of ASBO.
Some limitations exist in the present study. First, it was a retrospective single-center study with a small sample size, and therefore, it may be subject to selection bias. Second, there is no uni ed protocol for the treatment of ASBO in our institute. Generally, the obstruction continued for more than 1 week despite gastrointestinal decompression, or if it recurred after diet resumption, we performed elective surgery.
However, some patients with a high risk for surgery (e.g., old age and poor PS) were treated conservatively for longer than 1 week. Third, at our institute, patients with the closed loop sign on CT imaging generally underwent emergency surgery, even though it did not represent bowel ischemia.
Therefore, as aforementioned, the poor prognosis in female patients, which was revealed in this study, may not t ASBO with a closed loop sign.

Perspectives and signi cance
When considering the di culty of predicting the response to gastrointestinal decompression and LOS in ASBO, this result is of signi cant importance because it suggests that sex differences are possible surrogate markers to predict the prognosis of patients with non-strangulated ASBO. Further multicenter studies incorporating a larger number of patients are needed to de nitively con rm whether sex differences are associated with the prognosis of postoperative ASBO.

Conclusion
In conclusion, we found that female sex was associated with an increased odds of requiring elective surgery and prolonged LOS in patients with non-strangulated postoperative ASBO.

Declarations
Ethics approval and consent to participate This study was approved by the Ethical Committee of Shinshu University Hospital (approval number: 4864). Informed consent was obtained from each patient included in this study by using the opt-out method. The opt-out method was approved by the Ethical Committee of Shinshu University Hospital.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.