Gender Differences in Gastrointestinal, Hepatobiliary and Pancreatic Surgery and Perceived Relevance on Outcomes —A Single Center 22-Year Observational Study in India (1996-2018)

Introduction: Gender differences are still quite prevalent in the present time. Although there is literature regarding gender differences in healthcare ex-penditure in India, there is no data regarding gender differences in hospital stay, hospital seeking behaviors and mortality. Aim: To evaluate the Gender differences in a hospital seeking behavior, mortality and hospital stay. Methods: We prospectively analyzed, from a retrospective database, all patients who underwent surgical gastrointestinal, hepato-biliary, pancreatic and splenic surgeries from 1996 to 2018 in our unit. Patients were divided into groups based on gender, admission time period and priority of admission i.e., elective or emergency. Both the gender groups were compared with respect to total procedures done, hospital stay and mortality. Organ specific mortality was calculated as proportions, was analyzed and compared between the groups. Time trends of the same were observed and compared. Results: Of 12,411 patients, 7979 (64.3%) were males and 4432 (35.7%) were females. 9191 (74.1%) patients underwent elective procedures whereas 3220 (25.9%) had emergency procedures (p ≤ 0.001). Overall mortality was higher in males (n = 473, 5.92%) in comparison to females (n = 185, 4.17%) (p ≤ 0.001). Ma-jority of surgeries in males were of small intestine (22.5%) (34%) and for males, it was pancreatic surgery (37.3%). Highest mortality in males was emergency open pancreatic necrosectomy (21.6%) and that in females was emergency small intestinal surgery (11.9%). Although the number of surgeries in females increased over time (380 in 1996-1999 Vs 951 in 2016-2018), the proportion remained constant (36.3% Vs 38.3% in 1996-1999 and 2016-2018 respectively). Conclusion: We conclude that mortality is found to be higher in males after gastrointestinal surgery, which may be ex-plained by the fact that hospital seeking behavior is more in males though it is fairly increasing in females in the recent years.

groups based on gender, admission time period and priority of admission i.e., elective or emergency. Both the gender groups were compared with respect to total procedures done, hospital stay and mortality. Organ specific mortality was calculated as proportions, was analyzed and compared between the groups. Time trends of the same were observed and compared. Results: Of 12,411 patients, 7979 (64.3%) were males and 4432 (35.7%) were females. 9191 (74.1%) patients underwent elective procedures whereas 3220 (25.9%) had emergency procedures (p ≤ 0.001). Overall mortality was higher in males (n = 473, 5.92%) in comparison to females (n = 185, 4.17%) (p ≤ 0.001). Majority of surgeries in males were of small intestine (22.5%) in which small bowel resection was most commonly done (5.4%), whereas, gallbladder and biliary surgeries (27.4%) were the most common in females in which laparoscopic cholecystectomy was most commonly done (5.8%). Median hospital stay was higher in males (10 days vs 9 days), (p ≤ 0.001). Mortality was higher in females in all organ categories except in liver (6.34% vs 2.7%), pancreas (37.3% Vs 18.3%) and spleen (3.38% Vs 1.62%) where mortality was higher for male gender. Highest mortality for females was in small intestinal surgery

Introduction
Gender can be defined as "an array of socially constructed roles and relationships, personality traits, attitudes, behavior, values, relative power and influence that society ascribes to the two sexes on a differential basis. It is relational, because gender roles and characteristics do not exist in isolation, but are defined in relation to one another or through the relationships between women and men, girls and boys" [1].
Simply put, sex refers to biological differences and gender refers to social differences. In comparison, the average life expectancy is shorter for men than for women in almost all countries, but the magnitude of this advantage varies geographically and historically. This highlights the importance of understanding what causes gender differences in health. Although biological factors [2] and health behavior [3] may provide a partial explanation, it is very widely assumed that men and women have a different propensity to consult healthcare providers [4] and that this may be an important contributor to the gender gap in mortality [5]. However, many large-scale studies based on survey data have now reported greater use of primary healthcare services in women in western countries [4] [6].
Gender inequalities in one form or another, with considerable contextual differences, are ubiquitous and all-pervasive in South Asia. These are manifested as differences in mortality (observed by overall sex-ratio) medically. This is the observation seen in almost every country in this region. India is no exception in this regard.
Households and communities in India often place women in subordinate positions to men [7] [8]. In healthcare, girls are frequently neglected during the care-seeking process, and they experience relatively poorer nutrition, greater delays in receiving care, and lower access to preventative and curative care [9] [10].
Biologically, it has been observed in various recent studies that those of the female sex have a better mechanism of fighting stress than males most probably because of the influence of oestrogen on various aspects of the immune system. In most of these studies, males had a higher mortality rate compared to females. A recent review of the National Trauma Data Bank found that men were 14% more likely to die during their admission following a traumatic incident than women, a trend that was present from hospital day 1 and increased as length of stay increased [11]. A similar trend was seen in patients having traumatic brain injuries, where females showed a significantly lower mortality and rate of complications [12]. This gender disparity is also thought to be the result of the effects of oestrogen. Women under the age of 50 years, presumed to be premenopausal, had half the risk of death as age-matched men who had suffered from blunt trauma [13]. When adjusted for injury severity, these results persisted, and women still had a lower risk of mortality after traumatic injury and were also less likely to develop life-threatening complications [14].
The effects of oestrogen on different organs appears to be mediated by different receptors; oestrogen receptor-a mediates its effects on the Kupffer cells, alveolar and splenic macrophages, splenic T cells, and the small intestine, whereas oestrogen receptor-b mediates its effects on the heart, as well as the lung and small intestine [15]. This occurs through both a genomic, transcription-dependent mechanism as well as a non-genomic phosphorylation-dependent mechanism [16].
Gap in Knowledge Though there are many studies in the literature showing gender differences in the incidence of and in seeking health care in medical gastrointestinal (GI) disease, there is a paucity of data and literature in surgical GI diseases especially in the Indian subcontinent in the emergency and elective settings.
Our aim was to study gender differences in the mortality rate and duration of hospital stay and their trends since the inception of our department in 1996 until the end of 2018, just over two decades, and also to assess how hospital seeking behavior of males and females might have influenced these variables.

Patients and Methods
We analysed retrospectively, prospectively collected data of patients who had been admitted to our Department of Surgical Gastroenterology and Liver Trans-

Inclusion criteria
We included all patients who underwent surgical procedures in the emergency and elective settings.

Exclusion criteria
All patients with incomplete in-hospital data were excluded from the study. The primary outcome measured was gender difference in mortality and the secondary outcomes analyzed were gender differences in priority and types of operations done and organ systems involved, in-hospital stay and time trends in disease presentations. Patient demographic data, hospital stay, type of operation performed, post-operative morbidities, mortality and the time period were used as variables for analysis of outcomes.

Outcomes measured
Statistical analysis This was done using SPSS 25.0 version software. Continuous data were summarized as means with standard deviations or medians with inter quartile ranges. Categorical data were summarized as frequency with percentages and analyzed using chi-square/Fisher's exact test. Comparison of continuous data was done using the Mann-Whitney U test. For all tests a p value < 0.05 was considered to be statistically significant.
Bivariate analysis was performed for categorical dependent variables (death), and t-tests for continuous dependent variables (length of hospital stay). Multivariate analysis was performed using logistic regression for the primary and secondary outcomes.

Results
During the study period (1996 to 2018) a total of 12,411 patients underwent gastrointestinal, pancreatic and hepatobiliary procedures. They were divided into two groups based on gender and these two groups were found to be similar in age (p = 0.616) and co-morbidities. The number of gastrointestinal operations performed increased gradually over the years, but the time trends were similar in both groups. Although the number of operations in females increased over time (from 380 in 1996-1999 to 951 in 2016-2018) the proportion, when compared to males, remained constant (36.3% in 1996-1999 vs 38.3% 2016-2018). The demographic data are summarized in Table 1 and the time trends depicted in Figure  1. The time trends in gender differences are depicted in Table 2.
A total of 9191 (74%) patients underwent elective and 3220 (26%) had emergency procedures (p < 0.001). The number of males undergoing both elective and emergency procedures surpassed females by a wide margin (p < 0.001) -5694 (62%) males and 3497 (38%) females undergoing elective and 2285 (71%) males and 935 (29%) females emergency operations. However, the proportion of females undergoing emergency operations was significantly less than that for males (21% vs. 29%) (p < 0.001). The measured differences in gender among the elective and emergency procedures are depicted in Table 3. Table 4 displays the breakdown by the type of procedure that patients underwent. The most common procedure done in both males and females and in total (22%, n = 2748) was small intestinal followed by pancreatic (15%), colonic (14%) and gall bladder (12%) operations. While the largest number of procedures performed in males were on the small intestine (23%) in females the main procedures were on the gall bladder and biliary tract (27%) with small bowel resection being the most commonly performed (5.4%) in males and laparoscopic chole-cystectomy in females (5.8%)., Males underwent a higher proportion of duodenal, gastric, anal and pancreatic procedures compared to females while biliary and gall bladder surgeries were proportionately higher in females. Both sexes underwent equal proportions of colorectal, anal, oesophageal, small intestinal, splenic, liver and portal hypertension operations.     When the mortality rates in operations on the different organ systems were analyzed it was observed that females had higher death rates in all organ categories except in liver (6.3% vs 2.7%), pancreas (37% Vs 18%) and spleen (3.4% vs 1.6%) procedures where the mortality was higher in males. However, this difference in mortality rates was significant only in females in the liver and pancreas categories (p = 0.014 and p = 0.003 respectively). The highest mortality for females was in small intestinal surgery (34%) and for males it was pancreatic surgery (37%). Highest mortality in males was emergency open pancreatic necrosectomy (22%) and that in females was emergency small intestinal surgery (12%). These statistics have been clearly depicted in Table 6 and Figure 2.

Discussion
We found that after GI surgical procedures females fared better than males with respect to overall mortality and hospital stay. But the difference in mortality rates among the two fenders was not as significant as was found in other studies from the developed countries. Though statistically insignificant females in this study in fact had higher mortality rates than males when mortality rates after operations done on most of the different organ systems was considered. Females fared better than males only in the liver, pancreas and spleen organ systems categories.
It has been established through previous studies that gender and health are related in many different ways [18] [19] [20]. This also holds good when comparing the health seeking inclination of men and women. These differences depend on various facts like inter-gender relations, cultural notions and gendered differences in access to health care [21]. Studies from across the globe show that these differences change from region to region influenced by factors like power relations [22], structural positions [23], culturally prescribed gender roles [24] or economic factors apart from cultural context. Despite the interest in gender in other areas, there is a paucity of studies evaluating how gender may affect outcomes after gastrointestinal surgery. Among the few studies conducted, the conclusions vary mainly based on whether the study population is from developing or developed countries.
While most western studies found a higher hospital seeking behavior among females with women more likely to be having their operations performed in a teaching facility than men [17], the reverse is true in most studies from developing countries like India. Even in the present study, the number of females ad- According to some previous studies females from developing countries seek formal health care less than men [25] and prefer traditional healing options over them [26]. Harrison and colleagues [27], concluded in their study that, the gender socialization process, shaped by the socio-cultural ethos, also tends to impact health related notions and habits, including decisions regarding when and where to seek medical help.
According to another study by Valssof [28] the inferior status of women in a family or society also affects their decision-making regarding access to health care, education and economic resources. This is more pronounced in countries or communities with these kinds of structural restraints [29]. For example, in a study done in rural parts of Uttar Pradesh, Pune and West Bengal, it was found that health care for boys is traditionally given higher preference than health care for girls, in terms of money spent and accessing better health centers even if they need to travel greater distances to reach them [9] [30] [31].
A few recent studies however have shown that there is a slight decline in these gender differences in the recent years, with both men and women making almost similar use of formal and informal care [32]. However, in the present study, there was not much difference in the proportion of females getting admitted for gastrointestinal surgeries compared to men over the study period from 1996 to 2018 (36% in 1996-1998 vs. 38% in 2016-2018).
However, when biologically compared most studies conclude that females often fare much better than males with regards to all sorts of outcomes after gastrointestinal surgery or major trauma. These outcomes include mortality, duration of hospital stay, fewer emergency procedures and better outcome even after emergency operations. This advantage of the female gender has been attributed to the effects of oestrogen on the immune system [33]. In various previous studies it has been documented that males have poorer outcome compared to females after trauma or in the presence of sepsis [34] [35] [36] [37]. Even in this retrospective study, it was found that females had an overall lower in-hospital mortality rate compared to males (p < 0.001). Females also had a lesser mean duration of hospital stay compared to men (10.3 vs. 11.8 days; p < 0.001).
Oestrogen can modulate the immune system through its receptors on various immune cells including T-cells, monocytes and macrophages [38] [39] [40]. It causes changes in cytokine production, cell activation and proliferation. The gonadal hormones oestrogen and testosterone influence immune and cardiac function following trauma, haemorrhage and shock. It has been observed, in a study in mice, that females had a better immune response compared to their male and ovariectomized female counterparts following trauma and hemorrhage [41] [42]. This suggested that oestrogen might have a protective role in this type of injury [43]. There were also other studies which observed these differences in humans and mice after trauma-haemorrhage, with males having an increased incidence of MODS (Multiple Organ Dysfunction Syndrome) and sepsis [44]. In another clinical study patients with multiple injuries were evaluated and it was observed that females in the study had significantly lower levels of IL-6 and IL-8 in serum at an early stage and lower levels of IL-10 at a later stage after injury compared to males. Consequently, females maintained a better functional immune response following sepsis and had better survival rate than males after sepsis [45] [46]. Studies on gender difference in outcomes after gastrointestinal studies from the west also show a significantly improved mortality in women after different surgery types like gastric, small intestinal, large intestine, hepatic and pancreatic [9] [47]. But in our study males had significantly better survival rates after liver and pancreatic surgeries (p < 0.001) and, though not significant, had better a survival rate after splenic surgery. In all the other types of surgeries females had better survival rates but this was not statistically significant. This is probably because of the cultural constraints with females presenting later in the disease course in developing communities compared to females of the developed communities.
One study from Glasgow, Scotland also found that outcome after emergency surgeries was found to be dependent on gender with females having better outcomes. We found in that females had significantly lesser proportion of emergency surgeries compared to males (p < 0.001), but mortality after emergency surgeries though better in females was not significant (p = 0.056).

Conclusions
In conclusion, we found that though females fared better than males in outcomes after gastrointestinal surgeries, the difference was not significant as has been observed in the developed countries possibly because of our cultural gender differences in hospital seeking behavior. This higher mortality rate might probably also be because of higher number of males getting admitted in tertiary hospitals for treatment compared to females. Though the proportion of admitted patients who received treatment fluctuated over time, the proportion of women always remained lower than the proportion of men.
The effects of oestrogen on outcomes following injury are a growing area of research and further studies are required to firmly establish this relationship. But in developing countries like India, it is necessary to create policy approaches directed towards better communication and medical awareness to enhance the medical care we provide for females.

Limitations
This is a single, tertiary centre study and so probably the results cannot be applied to the Indian population. The differences in incidence of pre-operative or post-operative complications and hospital charges incurred between males and females were not evaluated which might be other interesting areas for future investigation. Also, the gender differences in outcomes among different age groups

Ethical Approval
The article has been submitted and the certificate will be uploaded in due time.

Conflicts of Interest
The authors of this study certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.