Parity and bladder cancer risk: a dose-response meta-analysis

Bladder cancer (BC) is one of the most common genitourinary malignancies in the United States, with an estimated 76, 960 newly diagnosed cases and 16 390 deaths in 2016 [1]. Incidence rate of BC is notably gender-specific with men having a 3~4 fold greater risk than women for developing the disease [1]. Given the evidence from current knowledge, the gender disparity of incidence rate for BC cannot be completely explained by known risk factors, such as cigarette smoking and occupation [2].

Although the exact biological mechanisms for the gender disparity in BC development and progression are not well established, some studies have suggested that sex hormones and their receptors may contribute to this difference [3–5]. During pregnancy, changes in maternal hormones, as well as physical structure changes in the pelvic or lower abdominal region following childbirth, may lead to etiological changes that decrease BC risk. Till date, numerous observational studies [6–11] have investigated the roles of reproductive factors, such as age at menarche and menopause, parity, age at first birth, and number of children, in the development of BC, but results have been inconsistent, probably because of limited sample size included each individual study. Although published reviews and meta-analyses have focused on this topic [12, 13], up to now, a comprehensive and quantitative assessment of the relationship between parity number and BC risk has not been reported.

Therefore, we find it necessary to further assess the relationship between parity and BC risk by conducting a meta-analysis of current epidemiologic studies and providing a quantitative dose-response analysis.

This study protocol was approved by the institutional review board at the West China School of Medicine before initiation and don’t need ethical standard statement.

We searched online databases MEDLINE and EMBASE for the studies assessing the relationship of parity and BC risk before Sep 2016, using the following terms with every possible combination considered: parity, pregnancy, reproductivity, fertility, bladder, genitourinary tract, cancer, carcinoma, tumor. We searched the references of all eligible publications to identify additional relevant publications. Studies were included if they met the following criteria: (1) the study had a prospective or case-control design; (2) the study evaluated the relationship between parity and BC risk; (3) data were provided or would allow the calculation of relative risk (RR) or odds ratio (OR) and a 95% confidence intervals (CI). Exclusion criteria were as follows: (1) was not involved with the associations between parity and BC risk; (2) non-human studies, reviews, and comments; (3) studies not reporting primary outcomes; (4) studies based on overlapping patients. When duplicate publications were identified or data in separate publications originated from the same cohort, we used the publication with the largest number of cases and the most applicable data.

Numerous epidemiological studies have focused on BC risk factors in order to explain the gender disparity in BC incidence, while there is also a great interest in identifying factors that affect the risk of BC among women. Although previous studies have reported on the associations between parity and BC, to the best of our knowledge, no other earlier studies have clearly documented a dose-response pattern between parity number and BC risk. In present study, we conducted a dose-response meta-analysis to characterize the association between parity and BC risk. Findings from the present study indicated that parous was significantly inversely associated with BC risk compared with nulliparous, especially for non-smokers. Overall, the risk of BC decreased by 24% for women who had given birth and 53% for those who had never smoked and were ever parous.

Although the exact mechanisms underlying this inverse association between parity and BC risk are not completely established, several potential mechanisms have been proposed. First, during pregnancy, estrogen and progesterone levels increase drastically and induce substantial alterations to the structure, function, and histology of the bladder [25], possibly affecting the development and progression of BC. Both estrogen and progesterone receptors are found in bladder tissues suggesting that endocrine regulation could directly influence BC development [26]. Shen et al. [27] found that antiestrogens have an inhibitory effect on the growth of BC cells in vitro, indicating that estrogens may increase the development and growth of bladder malignancies. Some research has reported that progesterone suppresses the activity of the estrogen receptor during pregnancy [28]. Therefore, estrogen and progesterone have an antagonistic effects on human cells. The substantial increased in their levels during pregnancy may responsible for the decreased risk of BC for women. Moreover, a hormone-related protective effect based on the prity number may mirror the lifetime period of lactation and prolonged oxytocin inhibition of steroid hormones [6].

Second, smoking habits may have influenced the incidence of BC in women with parity. It is well known that prenatal cigarette smoking exposure may cause detrimental effects on reproductive health [29]. Therefore, most smokers who prepare for pregnancy are more likely to quit smoking. Thus, compared with nulliparous female smokers, parous smokers who quit smoking may have a shorter smoking exposure history and reduction of pack years, and this may affect their BC risk. In addition, cumulative effect of abandon smoking following multiple pregnancies may also associate to decrease the subsequent risk of BC. The findings of our study suggest that the negative correlation between parity and BC appears more remarkable among women who were never exposed to cigarettes, with these parous women experiencing at least a 53% decreased risk of BC compared with nulliparous women. However, such a dramatic risk reduction was not apparent among smokers. The reasons for this results of subgroup analysis may be that the effect of smoking on BC is so huge that for the development of the disease minor influence factors such as parity are less relevant. In case of never smokers, these minor influence factors play indeed a role.

Third, structural changes in the pelvic organs and pelvic floor organization following pregnancy may induce a decreased risk for BC in parous women. Childbirth is an established risk factor for lower urinary tract dysfunction, such as increased urinary frequency, stress incontinence, and overactive bladder [30], but the possible relationship with BC remains unclear. It is well known that BC risk is related to the contact time of the urothelium with carcinogens in urine. Some study reported that increased water intake and urination frequency may lessen contact time of urinary carcinogens with urothelium of the bladder, thus, diminish the bladder cancer risk [31, 32]. Zhang et al. [31] found that increasing urination frequency during daytime was associated with decreased risk of bladder cancer. Silverman et al. [32] suggested that nocturia may be a powerful factor in reducing BC risk. Based on the results of above studies, we can be reasonable to assume that lower urinary tract dysfunction after childbirth has a protective effect on BC risk, and this may be associated with shorter duration of exposure to urine carcinogens in the bladder. Further research should verify this hypothesis.

Meta-analyses of observational studies are prone to confounding, selection, and information bias as the included observational studies and can present particular challenges that may distort the results. However, our study has some strengths. First, we searched 2 electronic databases, which ensured a broad scope, and we included seven cohorts and seven case-control studies that involved a total of 6,214 cases and 2,693,350 non-cases. This large sample size should have provided sufficient statistical power to detect this potential relationship. Second, to control misclassification, we conducted a dose-response meta-analysis. This is the most comprehensive meta-analysis evaluating the associations between parity and BC. Third, no publication biases were detected in present study and outcome may be unlikely to remain unreported as studies with complex assessment of exposure.

This current dose-response meta-analysis indicates that women with parity have an inversely associated BC risk compared with nulliparous women. The exact mechanism underlying this protective effect requires further investigation.