U-Shaped Association Between Serum 25-hydroxyvitamin D concentrations and Urinary Leakage Among Adult Females Aged 45 Years and Over in the United States: A Cross-Sectional Study

doi:10.21203/rs.3.rs-2972048/v1

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Research Article

U-Shaped Association Between Serum 25-hydroxyvitamin D concentrations and Urinary Leakage Among Adult Females Aged 45 Years and Over in the United States: A Cross-Sectional Study

https://doi.org/10.21203/rs.3.rs-2972048/v1

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published 23 Jan, 2024

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Background

The relationship between serum vitamin D status and urinary leakage (UL) among middle-aged females remains to be further studied. In this study, we aimed to evaluate the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with UL among American females ages 45 years and over.

Methods

We used seven cycles of the National Health and Nutrition Examination Survey (NHANES) with self-report UL data. A total of 9525 women, 45 years and older, were enrolled in this study. Univariate and multivariate logistic regression models and the smooth curve fitting were used to analyze the association between clinical UL and serum 25-hydroxyvitamin D [25(OH)D] concentrations.

Results

We observed a non-linear relationship between serum 25(OH)D concentrations and clinical UL. We found that when serum 25(OH)D concentration was higher than the inflection point 63.5, there was a positive correlation between serum 25(OH)D concentrations and clinical UL ([OR]: 1.007, 95%CI: 1.005–1.009, P < 0.01). However, when serum 25(OH)D concentration was lower than the inflection point 63.5, there was a negative correlation between serum 25(OH)D concentrations and clinical UL ([OR]: 0.993, 95%CI: 0.989–0.996, P < 0.01).

Conclusions

The association between serum vitamin D and the risk of UL followed an U-shaped relation among US middle-aged females, with an inflection point at 63.5 nmol/L serum 25(OH)D concentrations.

Serum 25-hydroxyvitamin D

Urinary leakage (UL)

National Health and Nutrition Examination Survey (NHANES)

US Middle-aged females

U-shaped association

Urinary leakage (UL) or urinary incontinence (UI) is a common, often inadequate treated condition that affects millions of American women [1] and the prevalence increases with age and vaginal delivery [2]. In a research population followed up for 8 years, an overall incidence rate of UI of 21.9% (95% CI, 19.6-24.2%) and a remission rate of 33.3% (30.1‐36.5%) were observed [3]. UL can result from age-related physiologic changes, urological or gynecological diseases, neurological illnesses, behavior patterns and functional decline frequently [4]. It affects personal health, reduces the quality of life, and increases the economic burden of individuals and society.

25-hydroxyvitamin D [25 (OH) D], the main stored form of serum 25(OH)D, is a fat-soluble substance that promotes calcium and phosphate absorption [5]. Serum 25(OH) D deficiency is a common risk factor for various diseases, including myasthenia gravis [6], type 2 diabetes [7], chronic kidney disease [8], cardiovascular disease [9], and asthma [10]. However, low levels of serum 25(OH)D which defined as serum 25-hydroxyvitamin D below 30 ng/ml influences more than two thirds of the U.S. adult population and about one billion individuals in the whole world [11, 12]. A number of studies have found that serum 25(OH)D is associate with many urological diseases, such as hyperuricemia [13], male lower urinary tract symptoms and benign prostatic hyperplasia [14], and urological cancer [15]. Additionally, several clinical trials examined the negative effects of serum 25(OH) D deficiency on pelvic floor muscle strength, which is one of the important components of pelvic floor support [16, 17].

Although some studies demonstrated that lower serum 25(OH)D concentrations were associated with UI [18, 19], the evidence proving the relationship between serum 25(OH)D status and UI is limited and confused. For example, a cross-sectional study found that there was very high prevalence of serum 25(OH)D deficiency in stress UI patients [19], while another study indicated that the risks of developing UI were not related to vitamin D intake categories in middle-aged and older women [20].

To address the above confuses in knowledge, based on data from the National Health and Nutrition Examination Survey (NHANES), we aimed to investigate the association of serum 25(OH)D concentrations with risk of UL among U.S. women age 45 and older.

2.1 | Study population

The National Health and Nutrition Examination Survey (NHANES) is performed by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC), consisting of approximately 10,000 persons every two years. The purpose of the survey is to produce national estimates representative of the general non-institutionalized civilian US population. It collected information on demographic data and health condition through interviews, physical examinations and laboratory tests. The institutional review board of the NCHS approved the NHANES study protocols and released the data while protecting the privacy of the participants. And all participants submitted written informed consent. In this study, we only used these data for analysis and reporting purposes. The NHANES data were available in the official NHANES website [21]. In this study, we conducted a secondary analysis of data from the seven cycles of NHANES with self-report UL (2005–2006, 2007–2008, 2009–2010, 2011–2012, 2013–2014, 2015–2016, and 2017–2018). Due to high incidence of UL in middle-aged and older women, we therefore included female participants over the age of 45 years old with complete UI and vitamin D data. The flowchart of participant selection was demonstrated in Fig. 1.

2.2 | Variables

In the NHANES 2005–2006, serum 25(OH)D concentrations were determined using DiaSorin radioimmunoassay kit (Stillwater, MN). Beginning in the 2007 to 2008 cycle, serum 25(OH)D concentrations were determined by a standardized liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Serum 25(OH)D data from NHANES 2005–2006 were converted to equivalent 25(OH)D measurements using the LC-MS/MS method by regression equations. More details can be found on the NHANES website [22]. In accordance with CDC recommendations, we used the LC-MS/MS-equivalent data for all analyze [22].

In addition, we extracted some covariates from the NHANES database, including age, race (White and Nonwhite), education, income, drink, smoke, BMI, diabetes, hypertension, hyperlipidemia, stroke, asthma, hysterectomy, pregnant and vaginal deliveries. UL was accessed in NHANES by a question, how often have urinary leakage (Question number: KIQ005). Participants who answered every day and/or night, a few times a week, a few times a month or less than once a month to this question were classified as UL.

2.3 | Statistical analysis

Data in this study were statistically analysed according to CDC guidelines. The serum 25(OH)D levels were modeled and analyzed in the form of continuous and categorical. We categorized serum 25(OH)D concentrations into four groups according to the Endocrine Society Clinical Practice Guidelines, as follows: severe deficiency (< 25.00 nmol/L), moderate deficiency (25.00-49.99 nmol/L), insufficient (50.00-74.9-9 nmol/L), and sufficient (≥ 75.0 0nmol/L). The selection of the correct sample weights for the analyses depends on the variables used. All the interview and MEC (Mobile Examination Center) exam weights covered in this study are available in the demographic files. We used mean and standard deviation to summarize the continuous variables, and frequency and percentage to summarize the categorical variables. To compare whether there were any statistical differences between different vitamin D groups, we used the weighted linear regression model for continuous variables and the weighted chi-square test for categorical variables. The relationship between UL and serum 25(OH)D levels were evaluated using univariate and multivariate linear regression models as follows: Unadjusted model: No adjustment; Adjusted model: Adjusted for age, race, education, income, BMI, drink, smoke, diabetes, hypertension, hyperlipidemia, pregnant and vaginal deliveries history. Multiple imputation was performed for covariates with missing values. The nonlinear relationship between serum 25(OH)D levels and UL was determined by a smooth curve fitting and a generalized additive model. The inflection point with the maximum model likelihood value is determined by the trial-and-error method, and the log-likelihood ratio test is performed for the one-line linear model and the two-piecewise linear model. All analyses were performed using software package R (http://www.R-project.org, The R Foundation). In this study, Two-sided P < 0.05 was considered statistically significant.

3.1 | Baseline characteristics

Between 2005 and 2018, a total of 9525 participants were finally enrolled in our analysis. The characteristic distribution of participants was presented in Table 1(according to serum 25(OH)D concentrations), Table 2 (according to UL) and Table 3 (according to severity of UL). Briefly, women with higher levels of serum 25(OH)D were more likely to be older, white race, lower BMI, higher levels of education and higher incomes (p < 0.01). Interestingly, serum 25(OH)D concentrations and following variables including hypertension and stroke and UL exhibit a non-linear relationship (Table 1). According to UL, we found females in UL group had higher serum 25(OH)D levels (p < 0.01) (Table 2). In addition, compared with mild UL group, the severe UL group patients showed a higher serum 25(OH)D levels (p < 0.01) (Table 3).

Table 1

Baseline characteristics of participants with UL according to serum 25(OH)D concentrations
Characteristic	Serum 25(OH)D concentrations (nmol/L)				P value	P for trend
Characteristic	< 25.00 (n = 353)	25.00–49.99 (n = 2204)	50.00–74.99 (n = 3084)	≥ 75.00 (n = 3884)	P value	P for trend
Age (mean (SD))^$	60.44 (10.13)	60.40 (10.66)	61.05 (10.71)	64.85 (10.83)	< 0.001	< 0.001
Race_2 = White (%)*	62 (17.6)	634 (28.8)	1309 (42.4)	2370 (61.0)	< 0.001	< 0.001
Education (%)*					< 0.001	< 0.001
College or above^$	125 (37.2)	839 (39.4)	1291 (43.2)	1967 (52.3)
High school or equivalent	175 (52.1)	947 (44.4)	1266 (42.4)	1446 (38.4)
Less than high school	36 (10.7)	346 (16.2)	430 (14.4)	350 ( 9.3)
Income (mean (SD))^$	2.01 (1.39)	2.26 (1.54)	2.49 (1.59)	2.88 (1.63)	< 0.001	< 0.001
Drink = Yes (%)*	112 (57.4)	684 (55.8)	939 (56.8)	1259 (61.8)	0.002	0.005
Smoke = Yes (%)*	162 (45.9)	909 (41.3)	1143 (37.1)	1478 (38.1)	< 0.001	0.016
BMI (mean (SD))^$	33.60 (9.12)	32.12 (7.79)	30.17 (7.02)	28.65 (6.84)	< 0.001	< 0.001
Diabetes = Yes (%)*	94 (26.7)	496 (22.5)	551 (17.9)	657 (16.9)	< 0.001	< 0.001
Hypertension = Yes (%)*	211 (59.9)	1214 (55.3)	1535 (49.8)	2162 (55.7)	< 0.001	< 0.001
Hyperlipidemia = Yes (%)*	150 (46.9)	910 (45.3)	1437 (50.4)	2028 (53.8)	< 0.001	0.001
Stroke = Yes (%)*	33 ( 9.3)	134 ( 6.1)	165 ( 5.4)	247 ( 6.4)	0.019	0.019
Asthma = Yes (%)*	68 (19.3)	348 (15.8)	483 (15.7)	615 (15.8)	0.36	0.478
Hysterectomy = Yes (%)*	127 (36.2)	748 (34.8)	1040 (34.5)	1485 (38.7)	0.001	0.115
Ever_pregnant_level (%)*					< 0.001	< 0.001
1 ~ 2	111 (33.9)	596 (29.7)	846 (30.2)	1260 (36.0)
3 ~ 5	157 (48.0)	1068 (53.1)	1531 (54.6)	1825 (52.1)
> 5	59 (18.0)	346 (17.2)	426 (15.2)	415 (11.9)
Vaginal_deliveries_level (%)*					< 0.001	0.004
0	52 (15.8)	309 (15.2)	374 (13.2)	462 (13.1)
1 ~ 2	121 (36.8)	711 (35.0)	1085 (38.4)	1492 (42.4)
3 ~ 5	131 (39.8)	825 (40.7)	1136 (40.2)	1346 (38.3)
> 5	25 ( 7.6)	184 ( 9.1)	231 ( 8.2)	216 ( 6.1)
UL_bin = Yes (%)*	191 (54.1)	1095 (49.7)	1530 (49.6)	2144 (55.2)	< 0.001	0.082
UL_level (%)*					< 0.001	0.144
Never	162 (45.9)	1109 (50.3)	1554 (50.4)	1740 (44.8)
less than once a month	40 (11.3)	293 (13.3)	410 (13.3)	572 (14.7)
A few times a month	50 (14.2)	321 (14.6)	456 (14.8)	664 (17.1)
A few times a week	40 (11.3)	195 ( 8.8)	285 ( 9.2)	397 (10.2)
Every day and/or night	61 (17.3)	286 (13.0)	379 (12.3)	511 (13.2)
Data are presented as mean ± SD or n (%) ; * represent χ2 test for categorical variables; $ Linear regression models for continuous variables; UL represent urinary leakage

Table 2

Baseline characteristics of participants with UL
Characteristic	Urinary leakage		P value
Characteristic	No (n = 4565)	Yes (n = 4960)	P value
Age (mean (SD))^$	61.62 (10.75)	63.17 (11.02)	< 0.001
Race_2 = White (%)*	1746 (38.2)	2629 (53.0)	< 0.001
Education (%)*			0.265
College or above	1990 (45.0)	2232 (46.6)
High school or equivalent	1859 (42.0)	1975 (41.2)
Less than high school	575 (13.0)	587 (12.2)
Income (mean (SD))^$	2.56 (1.64)	2.60 (1.59)	0.317
Drink = Yes (%)*	1373 (55.1)	1621 (61.9)	< 0.001
Smoke = Yes (%)*	1689 (37.0)	2003 (40.4)	0.001
BMI (mean (SD))^$	29.18 (7.01)	31.01 (7.59)	< 0.001
Diabetes = Yes (%)*	773 (16.9)	1025 (20.7)	< 0.001
Hypertension = Yes (%)*	2286 (50.2)	2836 (57.2)	< 0.001
Hyperlipidemia = Yes (%)*	2007 (47.3)	2518 (53.6)	< 0.001
Stroke = Yes (%)*	218 ( 4.8)	361 ( 7.3)	< 0.001
Asthma = Yes (%)*	619 (13.6)	895 (18.1)	< 0.001
Hysterectomy = Yes (%)*	1496 (33.4)	1904 (39.1)	< 0.001
Ever_pregnant_level (%)*			0.012
1 ~ 2	1388 (33.9)	1425 (31.3)
3 ~ 5	2102 (51.4)	2479 (54.5)
> 5	601 (14.7)	645 (14.2)
Vaginal_deliveries_level (%)*			< 0.001
0	621 (15.1)	576 (12.6)
1 ~ 2	1612 (39.2)	1797 (39.2)
3 ~ 5	1552 (37.7)	1886 (41.2)
> 5	332 ( 8.1)	324 ( 7.1)
VitD (mean (SD))^$	69.61 (30.19)	72.56 (32.57)	< 0.001
Data are presented as mean ± SD or n (%) ; * represent χ2 test for categorical variables; $ Linear regression models for continuous variables; UL represent urinary leakage

Table 3

Baseline characteristics of participants with UL level
Characteristic	Urinary leakage					P value
Characteristic	L0 (n = 4565)	L1 (n = 1315)	L2 (n = 1491)	L3 (n = 917)	L4 (n = 1237)	P value
Age (mean (SD))$	61.62 (10.75)	60.69 (10.54)	61.69 (10.73)	63.88 (10.91)	67.05 (10.84)	< 0.001
Race_2 = White (%)*	1746 (38.2)	701 (53.3)	739 (49.6)	476 (51.9)	713 (57.6)	< 0.001
Education (%)*						< 0.001
College or above	1990 (45.0)	701 (54.9)	655 (45.5)	398 (45.0)	478 (40.1)
High school or equivalent	1859 (42.0)	471 (36.9)	606 (42.1)	357 (40.4)	541 (45.4)
Less than high school	575 (13.0)	106 ( 8.3)	179 (12.4)	129 (14.6)	173 (14.5)
Income (mean (SD))$	2.56 (1.64)	3.00 (1.61)	2.62 (1.59)	2.43 (1.59)	2.25 (1.48)	< 0.001
Drink = Yes (%)*	1373 (55.1)	392 (62.0)	482 (62.0)	313 (63.5)	434 (60.8)	< 0.001
Smoke = Yes (%)*	1689 (37.0)	492 (37.4)	573 (38.5)	385 (42.0)	553 (44.7)	< 0.001
BMI (mean (SD))$	29.18 (7.01)	29.58 (7.12)	30.59 (7.03)	31.44 (7.26)	32.74 (8.57)	< 0.001
Diabetes = Yes (%)*	773 (16.9)	208 (15.8)	274 (18.4)	189 (20.6)	354 (28.6)	< 0.001
Hypertension = Yes (%)*	2286 (50.2)	667 (50.7)	795 (53.4)	526 (57.5)	848 (68.7)	< 0.001
Hyperlipidemia = Yes (%)*	2007 (47.3)	630 (50.7)	710 (50.2)	479 (55.4)	699 (59.2)	< 0.001
Stroke = Yes (%)*	218 ( 4.8)	61 ( 4.6)	93 ( 6.2)	63 ( 6.9)	144 (11.7)	< 0.001
Asthma = Yes (%)*	619 (13.6)	208 (15.8)	251 (16.9)	173 (18.9)	263 (21.3)	< 0.001
Hysterectomy = Yes (%)*	1496 (33.4)	435 (34.0)	536 (36.7)	361 (39.9)	572 (46.7)	< 0.001
Ever_pregnant_level (%)*						< 0.001
1 ~ 2	1388 (33.9)	441 (36.6)	430 (31.5)	227 (27.2)	327 (28.6)
3 ~ 5	2102 (51.4)	635 (52.7)	757 (55.5)	473 (56.7)	614 (53.6)
> 5	601 (14.7)	130 (10.8)	177 (13.0)	134 (16.1)	204 (17.8)
Vaginal_deliveries_level (%)*						< 0.001
0	621 (15.1)	198 (16.3)	166 (12.1)	94 (11.2)	118 (10.2)
1 ~ 2	1612 (39.2)	496 (40.9)	574 (41.8)	319 (37.9)	408 (35.3)
3 ~ 5	1552 (37.7)	463 (38.2)	549 (40.0)	354 (42.1)	520 (45.0)
> 5	332 ( 8.1)	56 ( 4.6)	84 ( 6.1)	74 ( 8.8)	110 ( 9.5)
VitD (mean (SD))$	69.61 (30.19)	73.01 (32.30)	72.85 (31.57)	72.99 (34.70)	71.41 (32.44)	< 0.001
Data are presented as mean ± SD or n (%) ; * represent χ2 test for categorical variables; ^$ Linear regression models for continuous variables; L0 represent Never; L1 represent less than once a month; L2 represent a few times a month; L3 represent a few times a week; L4 represent every day and/or night

3.2 | Vitamin D and UI

In our study, we used univariate and multivariate linear regression and constructed two main models and to explore the independent impact of serum 25(OH)D on UL. As a continuous variable, serum 25(OH)D was significantly correlated with UL in both unadjusted model (odds ratio [OR]: 1.004, 95%CI: 1.003–1.004, P < 0.01) and adjusted model ([OR]: 1.003, 95%CI: 1.002–1.004, P < 0.01). When we concluded serum 25(OH)D as a categorical variable, we found that the relationship between serum 25(OH)D levels and UI was non-linear. Compared with serum 25(OH)D severe deficiency groups, we found that those in the insufficient groups had 21.46% higher UL risk ([OR]: 1.2146, 95%CI: 1.006–1.460, P < 0.01) in the unadjusted model and 30.70% highe UL risk ([OR]: 1.307, 95%CI: 1.190–1.435, P < 0.01) in the adjusted model. However, compared with the vitamin D severe deficiency groups, the moderate deficiency groups showed an OR of 0.883 (95%CI: 0.786–0.993, P = 0.03) in the adjusted model (Table 4).

Table 4

Relationship between the serum 25(OH) D concentrations and UL in the unadjusted model and adjusted Logistic regression models
	OR (95% CI) P Value
Serum 25(OH)D concentrations	Unadjusted model ^a	Adjusted model ^b
25(OH) D (continuous)	1.004 (1.003, 1.004) < 0.01	1.0030 (1.002, 1.004) < 0.01
25(OH) D (categorical)
< 25.00	Reference	Reference
25.00–49.99	0.969(0.866, 1.086) = 0.587	0.883 (0.786, 0.993) = 0.03
50.00–74.99	1.2146 (1.006, 1.460) < 0.01	1.307 (1.190, 1.435) < 0.01
≥ 75.00	0.9521 (0.999, 1.084) = 0.633	1.014 (0.949, 1.083) = 0.67
^a Unadjusted model represent Crude model including 25(OH) D;
^b Adjusted model adjusted for sociodemographic variables (including age, race, education, income and BMI), drink, smoke, diabetes, hypertension, hyperlipidemia, pregnant and vaginal deliveries history

We therefore further analyze the relationship between serum 25(OH)D levels and UL among middle-aged and older U.S. females. The adjusted smooth curve fitting revealed the association between serum 25(OH)D levels and UL was non-linear after adjusting for age, race, education, income, BMI, drink, smoke, diabetes, hypertension, hyperlipidemia, pregnant and vaginal deliveries history (Fig. 2). In order to present the relationship accurately, we adopted two-piecewise binary logistic regression. Using trial and error method, the infection point was 63.5 nmol/L. When the serum 25(OH)D concentration was higher than the threshold of 63.5 nmol/L, it was positively correlated with the likelihood of UL ([OR]: 1.007, 95%CI: 1.005–1.009, P < 0.01). Whereas when the serum 25(OH)D concentration was lower than 63.5, it was negatively correlated with the likelihood of UL ([OR]: 0.993, 95%CI: 0.989–0.996, P < 0.01) (Table 5).

Table 5

Threshold effect analysis of the relationship between the serum 25(OH) D concentrations and UL in the unadjusted model and adjusted Logistic regression models
	OR (95% CI) P Value
Serum 25(OH)D concentrations	Unadjusted model ^a	Adjusted model ^b
25(OH) D < 63.5	0.995 (0.991, 0.998) < 0.01	0.993 (0.989, 0.996) < 0.01
25(OH) D ≥ 63.5	1.008 (1.006, 1.010) < 0.01	1.007 (1.005, 1.009) < 0.01
^a Unadjusted model represent Crude model including 25(OH) D;
^b Adjusted model adjusted for sociodemographic variables (including age, race, education, income and BMI), drink, smoke, diabetes, hypertension, hyperlipidemia, pregnant and vaginal deliveries history

In this cross-sectional study, we found that serum 25(OH)D, as a continuous variable, was significantly associated with UL after adjusting for other covariates. In the categorical variables, adjusted model results suggested that serum 25(OH)D also showed an independent effect on UL in middle-aged and older U.S. females. Furthermore, we observed a non-linear relationship between serum 25(OH)D levels and UL and identified the potential inflection point. The risk of UL was lowest when serum 25(OH)D concentrations were approximately 63.5nmol/L. Patients with serum 25(OH)D levels above or below 63.5nmol/L were at increased risk for UL. These results suggested that the independent relationship between serum 25(OH)D concentrations and UL is an approximately U-shaped curve. To the best of our knowledge, this is the first study revealing the relationship between serum 25(OH)D levels and clinical UL in a large cross-sectional study of middle-aged and older U.S. females.

We found that serum 25(OH)D concentrations was associated with BMI and race. Obese individuals have low levels of serum 25(OH)D because of increased storage and sequestration of serum 25(OH)D in adipose tissue [23]. The lower serum levels of 25(OH)D in African Americans than in whites are due to skin pigmentation, which reduces vitamin D production, and the reduced intake of dietary supplements in African Americans [24, 25]. In addition, we observed that the prevalence of UI was associated with age, vaginal delivery, obesity and education levels. Some structural and functional changes that occur in the bladder with age, such as increased involuntary detrusor muscle contraction and reduced bladder elasticity and compliance, may lead to UI [26]. Rortveit et al. revealed that women who deliver vaginally have a higher risk of UI [27]. Noblett et al. confirmed that obesity may put pressure on the pelvic floor in a state of chronic increased stress [28]. Kriss et al. [29] and Liu et al. [30] showed that lower education levels increased the odds of UI, but no definitive link has been found between education and incontinence.

Serum 25(OH)D has a crucial role in the development of UI. It is supposed to affect UI in females in a variety of ways. An immunohistological study by Bischoff et al. suggested the presence of 1, 25-dihydroxyvitamin D3 nuclear receptors in human skeletal muscle [31]. In addition, Badalian et al. found that higher vitamin D levels have been linked to a reduced risk of pelvic floor disease in women [16]. Moreover, Parker-Autry et al. found that insufficient vitamin D was significantly associated with weakness in the levator ani and coccygeus skeletal muscles, which are important components of the pelvic floor [32]. In conclusion, we suggested that low serum 25(OH)D levels may contribute to the development of urinary incontinence by causing pelvic floor muscle weakness. Specifically, pelvic floor muscle weakness may prevent women with UI from effectively closing the urethra when abdominal pressure increases, leading to stress urinary incontinence [33].

Another possible link between serum 25(OH)D levels and UI is inflammation. A common symptom of overactive bladder (OAB) syndrome is UUI. Cheung et al. found that the prevalence of UUI in patients with OAB is 82.9% [34]. Several studies suggested that inflammatory cytokines play a crucial role in the regulation of connexins expression and the pathogenesis of bladder dysfunction [35, 36]. And inflammatory cytokines were involved in overactive parasympathetic and peptidergic/sensory interactions with local immune cells [37]. Furthermore, Zhang et al. performed a cross-sectional analysis and revealed that more pro-inflammatory diets were associated with an increased likelihood of UI in American women younger than 65 [38]. Calton et al. performed a systematic review and suggested that appropriate levels of serum 25 (OH) D may be essential for the optimal anti-inflammatory response of immune cells[39]. Current evidence indicated serum 25(OH)D supplements have anti-inflammatory effects [39, 40]. Therefore, we believe that low serum 25(OH)D levels may contribute to the development of urinary incontinence through inflammation.

Stafne et al. conducted a cross-sectional study of 851 healthy, pregnant women and found that serum 25(OH)D < 50 nmol/L was associated with an increased risk of any UI, especially SUI [18]. Vaughan et al. performed a prospective cohort study of 350 community-dwelling older adults and indicated that cumulative event UI at 42 months was related to baseline serum 25(OH)D deficiency and showed a trend associated with deficiency [41]. In addition, a randomized controlled trial of 60 premenopausal women demonstrated that the number of SUI and urinary leakage symptoms decreased after vitamin D supplementation in the intervention group [42]. These findings are partially consistent with our finding of a negative correlation between serum 25(OH)D levels and UI. Another interesting finding is that the clinical UI increases when the serum 25(OH)D concentration exceeds the threshold. Unfortunately, very limited research has directly explored the connection between high levels of serum 25(OH)D and clinical UI. In addition, it is important to note that it is usually not possible to achieve serum 25(OH)D concentrations as high as 90 nmol/L through the usual dietary intake or food supplements [43].

Our research had several advantages. First, compared to previous similar studies, this study benefited from a large sample size from NHANES in which participants had well-documented serum 25(OH)D and UL data. Second, since this was an observational study susceptible to potential confounders, a multi-model logistic regression analysis was used to reduce residual confounders. Third, we used adjusted smooth curve fitting to visualize the association between serum 25(OH)D concentration and UL and performed threshold effect analysis.

Our study had some limitations. First, UL was collected through questionnaire survey, and there was inevitable recall bias. Second, our cross-sectional study revealed only this association, but a causal relationship between serum 25(OH)D and UL has not been validated. Third, because the study participants were limited to 9,525 American women age 45 and older, it cannot be generalized to men or people beyond the age range. Given these limitations, well-designed multicenter controlled trials are crucial for validating our research results.

Our cross-sectional study of a representative sample of women aged 45 and older in the United States suggested that there is a U-shaped relationship between serum 25(OH)D levels and UL. Serum 25(OH)D deficiency was associated with increased UL, independent of age and vaginal delivery. Increasing UL risk above the 25 (OH) D value of 63.5nmol/L remains to be explored. Future studies are necessary to evaluate the relationship between serum 25(OH)D and UI and elucidate the underlying mechanisms of these associations.

Ethics approval and consent to participate

The survey protocol was approved by the Ethics Review Board of the National Center for Health Statistics (NCHS), and each participant provided written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.

Acknowledgments

Not applicable

Authors’ contributions

Wenzhong zheng and Xiaoling Chen designed the research and revised the article for important intellectual content; Zeyu Li completed the data analysis and interpretation; Keshuai Zhang, Shuangyan Wu drafted the manuscript; Xinzhuo Lu downloaded the NHANSE data. All authors approved the manuscript submitted finally.

Funding

None

Availability of data and materials

All the data are publicly available online (https://www.cdc.gov/nchs/nhanes/)

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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U-Shaped Association Between Serum 25-hydroxyvitamin D concentrations and Urinary Leakage Among Adult Females Aged 45 Years and Over in the United States: A Cross-Sectional Study

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1 | Introduction

2 | Materials and Methods

2.1 | Study population

2.2 | Variables

2.3 | Statistical analysis

3 | Results

3.1 | Baseline characteristics

3.2 | Vitamin D and UI

4 | Discussion

5 | Conclusion

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