Risk of Urinary Tract Infection and Asymptomatic Bacteriuria among Diabetic and Nondiabetic Postmenopausal Women

Edward J. Boyko1,2, Stephan D. Fihn2,3, Delia Scholes4,5, Linn Abraham5 and Barbara Monsey5

1 Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, WA
2 Department of Medicine, School of Medicine, University of Washington, Seattle, WA
3 Northwest Health Services Research and Development Program, VA Puget Sound Health Care System, Seattle, WA
4 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA
5 Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, WA

Correspondence to Dr. Edward J. Boyko, VA Puget Sound Health Care System (S-152E), 1660 South Columbian Way, Seattle, WA 98108 (e-mail: eboyko{at}u.washington.edu).

Received for publication February 2, 2004. Accepted for publication October 26, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
No prospective data exist on the risk of microbiologically confirmed urinary tract infection (UTI) and asymptomatic bacteriuria (AB) in relation to diabetes mellitus and its characteristics. The authors prospectively (1998–2002) followed 218 diabetic and 799 nondiabetic Washington State women aged 55–75 years for UTI and AB. The baseline examination and two annual follow-up examinations included urine culture, measurement of hemoglobin A1c and postvoid residual bladder volume, and a survey of diabetes and other characteristics. Surveillance for UTI included self-reports confirmed by microbiologic culture and medical record review. UTI incidence per 100 person-years was 12.2 for diabetic women and 6.7 for nondiabetic women (relative risk (RR) = 1.8, 95% confidence interval (CI): 1.2, 2.7). AB incidence per 100 person-years was 6.7 for diabetic women and 3.0 for nondiabetic women (RR = 2.3, 95% CI: 1.3, 3.9). In Cox models adjusted for multiple covariates, the increased UTI risk occurred mainly in women taking insulin (RR = 3.7, 95% CI: 1.8, 7.3) and women with a longer diabetes duration (≥10 years; RR = 2.6, 95% CI: 1.3, 5.1) compared with nondiabetic women. No clear linear trend between hemoglobin A1c and UTI or AB risk was seen. Postmenopausal women with diabetes have higher risks of UTI and AB in relation to diabetes duration and severity but not to recent glucose control.

diabetes mellitus; postmenopause; prospective studies; risk factors; urinary tract infection; women


Abbreviations: GHC   Group Health Cooperative of Puget Sound; UTI   urinary tract infection


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Urinary tract infection (UTI) accounts for considerable morbidity among adult women; it is responsible for 3.6 million office visits annually in the United States and direct costs of $1.6 billion (1Go, 2Go). The belief that diabetes mellitus, which is estimated to affect 16 million persons in the United States, predisposes to UTI is widespread (3Go, 4Go). Diabetes causes several abnormalities of the host defense system that might result in a higher risk of certain infections, including UTI (5Go). These include immunologic impairments, such as impaired migration, intracellular killing, phagocytosis, and chemotaxis of polymorphonuclear leukocytes from diabetic patients (6Go), and neuropathic complications, such as impaired bladder emptying (7Go). In addition, a higher glucose concentration in the urine may create a culture medium for pathogenic microorganisms.

Although the relation between diabetes and asymptomatic bacteriuria has been the subject of several controlled studies, the association between diabetes and UTI risk has not been examined until recently. A case-control study of postmenopausal women demonstrated 2.2-fold relative odds of microbiologically confirmed UTI in relation to diabetes mellitus. This increase in risk was confined mainly to women undergoing pharmacologic treatment for diabetes (8Go). A randomized controlled trial of the effects of hormone therapy on coronary heart disease events among 2,763 postmenopausal women aged 44–79 years with established coronary heart disease showed a significant 1.4- to 1.8-fold increase in the risk of physician-diagnosed UTI in association with self-reported diabetes (9Go).

Given that a uniform screening process was not used in either of those studies, the possibility exists that a higher level of UTI detection occurred in women with recognized diabetes which led to an apparently higher risk of UTI in relation to this metabolic condition. Other important unanswered questions include the association between glycemic control and risk and the role of asymptomatic bacteriuria as a precursor to UTI in diabetic women.

To address these issues, we conducted a prospective study of postmenopausal women to investigate the relation of clinically confirmed diabetes to the risks of UTI and asymptomatic bacteriuria.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Study setting and participants
The study was conducted at the Group Health Cooperative of Puget Sound (GHC), a staff-model nonprofit health maintenance organization with approximately 450,000 enrollees. Women aged 55–75 years were eligible to participate if they resided in Pierce County, King County, or Snohomish County in Washington State, had been enrolled in GHC for at least 1 year, had not had a natural menstrual cycle in the preceding 12 months, and had not had a UTI in the preceding 90 days.

Women were randomly selected from the GHC enrollment file. We also selected additional women from the GHC Diabetes Registry who were frequency-matched, by age, to the main cohort. Exclusion criteria included residential nursing care, wheelchair dependency, dementia, severe psychiatric disorder, urinary catheterization, renal dialysis, active nonskin cancer, and chronic antibiotic use. After checking GHC databases for indicators of ineligibility, we contacted potential participants by letter and telephone to determine their eligibility and willingness to participate. We made up to 10 attempts to reach each woman by phone. The study protocol was approved by the human subjects committees of the University of Washington and GHC. Signed informed consent was obtained from all participants.

Women who participated were followed prospectively for 2 years. Exposure and outcome data were collected from multiple sources: interviews and research clinic visits conducted at baseline and at 12 and 24 months and GHC laboratory, hospital, and pharmacy data (for identification and verification of UTI and diabetes).

Primary exposures of interest included diabetes presence and characteristics, demographic features, sexual activity, and bladder function. The primary outcome of interest was acute UTI, as defined by a midstream urine specimen yielding ≥100,000 colony-forming units per ml of a uropathogenic organism (any aerobic gram-negative rod, Lancefield group B or D streptococci, or Staphylococcus saprophyticus), accompanied by dysuria, urgency, or frequency for 2 weeks or less.

We collected interview data at baseline and at 12 and 24 months between 1998 and 2002 to assess history of UTI, diabetes presence and characteristics, and sexual activity. Women who reported having diabetes were invited to complete a supplemental questionnaire that obtained data on age, weight, and height at onset of diabetes, history of ketoacidosis, and type of diabetes.

During research clinic visits, women underwent measurement of postvoid residual bladder volume using a portable ultrasound device (BladderScan BVI 2500; Diagnostic Ultrasound Corporation, Seattle, Washington) and submitted clean-catch midstream urine specimens for microbiologic culture. The presence of diabetes was ascertained by self-report of a physician's diagnosis. In addition, women who did not self-report diabetes but were included in the GHC Diabetes Registry were considered to have diabetes. This registry captures information from GHC laboratory, pharmacy, and hospital discharge summary databases at monthly intervals to continuously update the diabetes status of enrollees. Subjects are entered into this registry for specified time periods (indicated in parentheses) if they meet the following criteria: 1) a hospital discharge diagnosis of diabetes at any time (indefinite); 2) a random plasma glucose level greater than 200 mg/dl (12 months); 3) a fasting plasma glucose level greater than 125 mg/dl (12 months); 4) a hemoglobin A1c concentration greater than 7.0 percent (12 months); and 5) receipt of a prescription for insulin or an oral hypoglycemic agent (3 years). The presence of diabetes in women from the GHC Diabetes Registry was confirmed by record review. For identification of previously undiagnosed diabetes, fasting plasma glucose was measured at baseline, and a level greater than 125 mg/dl was defined as diabetes. Women meeting diabetes criteria underwent high-pressure liquid chromatography testing of hemoglobin A1c at baseline and at 12 and 24 months (Variant II hemoglobin A1c; Bio-Rad, Hercules, California). Women who reported an age of diabetes onset of less than 30 years, one or more episodes of ketoacidosis, and continuous use of insulin since diagnosis were considered to have type 1 diabetes.

Symptomatic UTI surveillance
Participants were instructed to contact research personnel if any new symptom occurred that suggested UTI. A standardized interview was then conducted, and, if infection was thought to be likely (presence of dysuria, urgency, or frequency), the patient was asked to provide an Oxoid dip-slide (Unipath, Ogdensburg, New York) urine specimen via mail, which was processed to identify and quantify uropathogens. The subject was also referred to her primary physician for evaluation.

In addition, surveillance of GHC clinical records was performed on a monthly basis to capture episodes of symptomatic UTI not reported to research staff. GHC diagnosis codes generated by outpatient clinical encounters and laboratory databases were searched for urinalysis results suggestive of infection (trace blood or any bacteria) or urine culture results indicative of infection; if such results were present, these women were interviewed by telephone for the presence of UTI symptoms. If the women were symptomatic, they were asked to send a dip-slide urine specimen to us for microbiologic culture.

Statistical methods
The primary outcomes of interest were episodes of asymptomatic bacteriuria and UTI during the follow-up period. We assessed the statistical significance of differences in means or frequencies of baseline characteristics by diabetes status using the t test or the chi-squared test (10Go). We computed incidence, incidence density ratios, and 95 percent confidence limits for first UTI according to risk factors of interest using standard methods (11Go). Cox proportional hazards modeling was used to estimate hazard ratios for UTI and asymptomatic bacteriuria while adjusting for covariates. Since multiple occurrences of UTI were included in these models, we used the Anderson-Gill model with a correction to the variance for multiple observations per woman (12Go, 13Go). The assumption of proportional hazards was tested in all Cox models and found to be valid (14Go). Women with asymptomatic bacteriuria at baseline were excluded from analyses of asymptomatic bacteriuria risk during the 2-year follow-up. We planned the study with a target sample size of 800 nondiabetic women and 200 diabetic women to achieve 80 percent power to detect a relative risk of 2.2 in relation to diabetes, assuming an annual UTI incidence of 3 percent and a two-sided alpha value of 0.05.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
A total of 799 nondiabetic women and 218 diabetic women agreed to participate, representing 34 percent and 26 percent of the total number of eligible nondiabetic and diabetic women, respectively. The random subject sampling method yielded 65 diabetic women from the GHC enrollment file, to whom an additional 153 women were added by random selection from the diabetes registry. A high proportion of participants completed the 12- and 24-month follow-up visits (87 percent and 81 percent, respectively).

Diabetic women were more likely to be non-White, slightly older, less educated, of lower income, and less sexually active and more likely to have a prior UTI than nondiabetic women (table 1). Diabetic women had a greater mean residual bladder volume (49.1 ml vs. 33.1 ml; p = 0.022) and were more likely to have a residual bladder volume greater than 200 ml (7.4 percent vs. 2.8 percent; p = 0.003). Forty-six women had asymptomatic bacteriuria at the baseline examination; frequencies of this condition were similar by diabetes status (diabetes absent, 4.0 percent; diabetes present, 6.5 percent; p = 0.138).


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TABLE 1. Characteristics of women with and without diabetes mellitus, Group Health Cooperative of Puget Sound, 1998–2002

 
Among nondiabetic women, 71 developed UTI during follow-up, with 55 (6.9 percent) having one episode, nine (1.1 percent) having two episodes, and seven (0.9 percent) having three or more episodes. Among diabetic women, 26 developed UTI, with 16 (7.3 percent) having one episode, seven (3.2 percent) having two episodes, and three (1.4 percent) having three or more episodes. Regarding diabetes characteristics, 30.1 percent of diabetic women had had the disease for 10 years or more, 1.4 percent had type 1 disease, 48.6 percent took oral hypoglycemic medication, and 19.0 percent used insulin.

Diabetic women had significantly higher risks of overall UTI and a first episode of asymptomatic bacteriuria (table 2). No distinct linear trend was seen between categorized hemoglobin A1c levels using two different sets of cutpoints and risk of either asymptomatic bacteriuria or UTI. Higher risks of UTI and asymptomatic bacteriuria were seen in diabetic women treated with medication, but statistical significance was observed only in the insulin-treated women. Significantly higher risks of asymptomatic bacteriuria and UTI were seen among women who had had diabetes for 10 or more years.


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TABLE 2. Incidence of and incidence ratios for all episodes of symptomatic urinary tract infection and a first episode of asymptomatic bacteriuria, by diabetes status and characteristics at the time of study entry, Group Health Cooperative of Puget Sound, 1998–2002

 
Multivariable failure-time analyses were performed to adjust for age, history of previous UTI, sexual activity, baseline asymptomatic bacteriuria, postvoid residual bladder volume, and ethnicity (table 3). All episodes of UTI and the first episode of asymptomatic bacteriuria were considered as outcomes. In unadjusted analyses, diabetes was related to a significantly higher risk of both outcomes, but this difference diminished for UTI after adjustment. The significant association between diabetes and higher risk of asymptomatic bacteriuria remained largely unchanged after additional adjustment for postvoid residual bladder volume and ethnicity.


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TABLE 3. Hazard ratios for asymptomatic bacteriuria and symptomatic urinary tract infection according to diabetes status and characteristics, Group Health Cooperative of Puget Sound, 1998–2002*

 
A weak trend was seen between hemoglobin A1c and risk of asymptomatic bacteriuria or UTI in adjusted models (table 3). However, no category of hemoglobin A1c was associated with a significantly elevated risk of UTI (except for >7.9 percent), while the lowest and highest categories were associated with a significantly higher risk of asymptomatic bacteriuria in one scheme and the middle and highest categories were associated in the other scheme. A significantly higher risk of UTI was seen among insulin-treated women. A significantly higher risk of asymptomatic bacteriuria was seen with insulin treatment but also with oral medication use in a model adjusted for all covariates. When oral medication treatment was set as the reference category, insulin therapy was associated with a significantly higher risk of UTI compared with oral medication in a model adjusted for all covariates (relative risk = 2.9, 95 percent confidence interval: 1.2, 6.9). Higher risks of UTI and asymptomatic bacteriuria were seen only among women with a longer duration of diabetes.

Uropathogens observed in UTI did not differ by diabetes status (diabetic women vs. nondiabetic women: Escherichia coli, 74.4 percent vs. 75.8 percent; Klebsiella sp., 7.0 percent vs. 6.3 percent; Proteus sp., 7.0 percent vs. 5.3 percent; group B Streptococcus, 2.3 percent vs. 3.2 percent; Enterococcus sp., 0 percent vs. 5.3 percent; other organisms, 9.3 percent vs. 9.3 percent (p = 0.863)). Bacterial pathogens other than E. coli were more often responsible for the first observed episode of asymptomatic bacteriuria in diabetic women (diabetic women vs. nondiabetic women: E. coli, 56.5 percent vs. 78.0 percent; Klebsiella sp., 21.7 percent vs. 9.8 percent; Proteus sp., 0 percent vs. 0 percent; group B Streptococcus, 4.3 percent vs. 4.9 percent; Enterococcus sp., 13.0 percent vs. 4.9 percent; other organisms, 4.3 percent vs. 2.4 percent (p = 0.071)).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
We observed a higher risk of acute symptomatic UTI and asymptomatic bacteriuria among postmenopausal women with diabetes. Women taking insulin were mainly those at higher risk, possibly because of more severe diabetes, since the use of insulin may be a marker for disease severity (15Go). Risk of UTI was higher with increasing duration of diabetes. The risk of incident asymptomatic bacteriuria was significantly increased in relation to insulin use in all multivariable models and to oral medication use in one model. Consistent with one other study, we found no significant association between glycemic control as assessed by hemoglobin A1c level and risk of UTI, while the pattern of risk elevation for the relation of asymptomatic bacteriuria to hemoglobin A1c was inconsistent with a dose-response effect (16Go). The high proportion of diabetic woman-years (67 percent) in the lowest hemoglobin A1c category (<7.5 percent) may have impaired our ability to detect this association in this analysis. Recategorization of hemoglobin A1c values (tables 2 and 3) to redistribute more woman-years to higher exposure categories did not produce a clearer dose-response effect.

The association between diabetes and risks of UTI and asymptomatic bacteriuria could not be explained by confounding due to frequency of sexual intercourse (a major risk factor for UTI (17Go)), a history of UTI, postvoid residual bladder volume, or ethnicity. The presence of asymptomatic bacteriuria at baseline did not confound the association between diabetes characteristics and UTI risk. Although diabetic persons may be more susceptible to infection by uncommon organisms, we found most of their infections to be due to typical uropathogens, which suggests that diabetes facilitates the same route of infection as that for UTI in nondiabetic persons (i.e., ascending infection from the urethra). The finding that asymptomatic bacteriuria more often involved Klebsiella and Enterococcus in diabetic women suggests that defenses against these organisms may be reduced. Geerlings et al. (18Go) found similar virulence determinants in E. coli isolated from women with and without diabetes.

Regarding potential mechanisms, we found that diabetic women had a higher mean postvoid residual bladder volume, an indicator of bladder dysfunction and possibly autonomic neuropathy (7Go). Adjustment of the diabetes-UTI (and asymptomatic bacteriuria) association by postvoid residual bladder volume had little effect on these associations. Thus, the main effects of diabetes on risks of asymptomatic bacteriuria and UTI are probably not mediated by postvoid residual bladder volume.

We found that baseline asymptomatic bacteriuria, a known risk factor for UTI, did not explain the higher risk of UTI among diabetic women (19Go, 20Go). Adjustment for asymptomatic bacteriuria in regression models of UTI risk and diabetes characteristics, including insulin treatment and duration, had little effect on these hazard ratios.

With the exception of two previous studies that examined UTI risk in relation to presence of diabetes, much of the pertinent literature has focused solely on bacteriuria (8Go, 9Go). A number of cross-sectional studies of bacteriuria and diabetes have been published (21Go). Of 12 reviewed studies, 75 percent reported a two- to fourfold higher prevalence of bacteriuria in diabetic subjects as compared with controls (22Go–33Go). Two of these studies demonstrated higher bacteriuria prevalence with increasing diabetes duration but no association with glycosylated hemoglobin level (23Go, 31Go), which is consistent with our findings.

We took precautions to minimize potential bias in this study. To prevent misclassification of UTI, we used a case definition that is more than 95 percent specific for this diagnosis (34Go) and confirmed the diagnosis using data from medical records, laboratory files, dip-slide culture, and patient interviews. To avoid the biases associated with selection of study subjects from clinical settings, we randomly selected these women from the entire GHC enrollment population in the targeted counties. Fewer than half of the eligible subjects agreed to participate given the requirement for ongoing surveillance and follow-up examinations. Since only subjects without chronic urinary voiding conditions or UTI were eligible for recruitment, it is unlikely that the participation rate caused biased associations between the main exposures and outcomes of interest, although a possible factitious association between higher UTI risk and diabetes might have occurred if diabetic women with a history of UTI were more likely to participate. The proportion of women completing follow-up was high. Given that the population was mainly Caucasian, the results may not be generalizable to other ethnic groups.

A major advantage of this study is that it reflects the influence of diabetes and other risk factors on risks of UTI and asymptomatic bacteriuria in a population-based sample of generally healthy, community-dwelling women. Although similarly intense surveillance methods were employed for UTI detection, it is possible that clinical providers had a lower threshold for the evaluation of possible UTI symptoms, thereby leading to a higher rate of this outcome in diabetic women. This same bias would not apply to the detection of asymptomatic bacteriuria, and the higher risk of asymptomatic bacteriuria that we observed in relation to diabetes argues in favor of causation as opposed to surveillance bias as the explanation for these findings.

The hemoglobin A1c measurements used to assess glucose control were obtained at baseline and the annual follow-up visits. It is possible that these measurements did not reflect glucose control throughout the entire year between follow-up examinations, though this seems unlikely on the basis of our data. We observed high correlations between year 1 and year 2 hemoglobin A1c measurements (correlation coefficient = 0.64) and between year 2 and year 3 hemoglobin A1c measurements (correlation coefficient = 0.61) and small mean differences and standard deviations (year 2 minus year 1: 0.4 percent (standard deviation, 1.3); year 3 minus year 2: –0.1 percent (standard deviation, 1.3)). However, the possibility exists that degree of hyperglycemia was not accurately captured for UTIs occurring more than 90 days before the time of hemoglobin A1c measurement and that more frequent performance of this test would have demonstrated an association between risk of this outcome and glycemic control.

The exact onset of type 2 diabetes cannot be easily determined, since symptoms may remain occult for years (35Go). Error in estimating diabetes duration due to this problem is likely to have been nondifferential, thereby resulting in underestimation of effects associated with this exposure. Given our screening protocol, it is unlikely that diabetes was also present among women not reporting this condition (36Go). Although our cohort was relatively large for a study of UTI epidemiology, it is possible that it was of insufficient size for detection of all clinically significant associations. It is also possible that the increase in UTI risk related to diabetes would be even greater in diabetic populations with poorer glycemic control.

In conclusion, diabetes treated with insulin and diabetes of longer duration were related to substantial increases in the risks of UTI and asymptomatic bacteriuria among postmenopausal women enrolled in the GHC health plan. Predictors of UTI and asymptomatic bacteriuria were similar, with the exception that diabetes was significantly related to risk of asymptomatic bacteriuria but not UTI. The higher risk of UTI was not explained by poorer glucose control, higher postvoid residual volume, or asymptomatic bacteriuria at baseline. UTI and asymptomatic bacteriuria should be considered complications of diabetes mellitus in postmenopausal women. These results also argue for diabetes severity and duration as the main determinants of higher UTI and asymptomatic bacteriuria risk—a pattern that resembles the relation between diabetes characteristics and other complications, such as retinopathy or neuropathy (36Go). Therefore, one would expect that improved diabetes control might yield a reduction in incidence of these complications, although this remains to be demonstrated in properly conducted randomized controlled trials.


    ACKNOWLEDGMENTS
 
Funding for this study was provided by National Institutes of Health grant RO1 DK43134. Drs. Fihn and Boyko received salary support from the US Department of Veterans Affairs.

The National Institutes of Health had no role in the study design, data collection, analysis, or interpretation of results or in the writing of this report.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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