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ORIGINAL RESEARCH |
From the University of California, San Francisco, California; Cedar-Sinai Medical Center, Los Angeles, California; and University of Michigan, Ann Arbor, Michigan.
Address reprint requests to: Jeanette S. Brown, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, Mount Zion Women’s Health, 2330 Post Street, Suite 200, San Francisco, CA 94115; E-mail: brownj{at}obgyn.ucsf.edu.
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ABSTRACT |
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METHODS: We used data from the Heart and Estrogen/ Progestin Replacement Study, a randomized, blinded trial of the effects of hormone therapy on coronary heart disease events among 2763 postmenopausal women aged 44–79 with established coronary heart disease. Participants were randomly assigned to 0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate or placebo and followed for a mean of 4.1 years. History of physician-diagnosed urinary tract infections and risk factors were assessed by self-report at baseline and each annual visit.
RESULTS: Urinary tract infection frequency was higher in the group randomized to hormone treatment, although the difference was not statistically significant (odds ratio [OR] 1.16, 95% confidence interval [CI] 0.99, 1.37). Statistically significant risk factors for urinary tract infections in multivariable analysis included: women with diabetes on treatment (insulin OR 1.81, 95% CI 1.40, 2.34), oral medications OR 1.44, 95% CI 1.09, 1.90), poor health (OR 1.34, 95% CI 1.14, 1.57), childbirth (OR 1.38, 95% CI 1.00, 1.90), vaginal itching (OR 1.63, 95% CI 1.07, 2.50), vaginal dryness (OR 1.30, 95% CI 1.04, 1.67), and urge incontinence (OR 1.51, 95% CI 1.30, 1.75). Urinary tract infections in the previous year were strongly associated with a single urinary tract infection (OR 7.00, 95% CI 5.91, 8.29) as well as multiple urinary tract infections (OR 18.51, 95% CI 14.27, 24.02).
CONCLUSIONS: Oral hormone therapy did not reduce frequency of urinary tract infections. Potentially modifiable risk factors in postmenopausal women are different from those in younger women, and include diabetes, vaginal symptoms, and urge incontinence.
Urinary tract infection occurs frequently among adult women of all age groups, the estimated incidence based on self-report of physician diagnosis being 11% per year.1 This incidence peaks during ages 18–24 at 17.5%, but is still a substantial 9% for women 50 and over.1
After menopause, the vagina is more likely to be colonized with potential uropathogens such as Escherichia coli, and vaginal pH rises as the lactobacillus no longer predominates.2 These observations have led investigators to propose hormonal treatment, which reestablishes the premenopausal flora, as a therapy to prevent recurring urinary tract infections. Although vaginal estrogen has been shown to reduce the rate of recurring urinary tract infections in two controlled trials,2,3 the role of oral hormone therapy remains unclear.1,4–6
Postmenopausal women may have different risk factors for urinary tract infections than premenopausal women. The most common cause among younger women, sexual intercourse, does not appear to be associated with urinary tract infections after menopause.7,8 Urinary incontinence, anatomic changes such as a cystocele, and diabetes are among the risk factors for recurrent urinary tract infections in older women.8,9
In this study, we examined urinary tract infections reported by 2763 women participating in the Heart and Estrogen/Progestin Replacement Study, a randomized, blinded trial, which compared the effects of 4 years of treatment with either conjugated estrogens (0.625 mg daily) plus medroxyprogesterone acetate (2.5 mg daily) or identical placebo. The randomized clinical trial design allowed for a rigorous assessment of the influence on urinary tract infections of oral hormone therapy after menopause, and the follow-up information on the cohort provided a strong observational design for examining risk factors for urinary tract infections among postmenopausal women.
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MATERIALS AND METHODS |
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At baseline, participants completed a questionnaire to ascertain their age, ethnicity, marital status, parity, years since menopause, chronic medical illnesses including diabetes, and overall self-reported health status (excellent, good, fair, poor, or very poor). Women who reported a diagnosis of diabetes were asked the type of medication they took (pills or insulin), if any, to control their disease.
At baseline and at each annual visit, participants also reported vaginal/genital symptoms in the last week including itching, dryness, or discharge (all, most, a good bit, some, little, or none of the time), and frequency of sexual activity (any sexual activity that is sexually arousing) in the last 6 months (more than once a week, once a week, two to three times per month, about once a month, less than once a month, or not at all). Additionally, smoking habits (current, former, or never, and number of cigarettes per day), and alcohol consumption (drinks per week) were assessed. Body weight, waist, and hip circumference were measured, and body mass index and waist-to-hip ratio were calculated. Fasting glucose measurements were obtained at the baseline and first annual visit. A woman was considered to have diabetes if she self-reported having physician-diagnosed diabetes, or took diabetes medication, or had a fasting glucose of greater than or equal to 126 mg/dL.
At baseline and each annual visit, participants were also asked a similar question on urinary tract infections as was used in the Third National Health and Nutrition Examination Survey,12 "During the past year, how many times has a doctor told you that you had a urinary tract infection?". A number of studies have demonstrated that a woman seeking care for a urinary tract infection has a 60–80% prevalence of urinary tract infections.13–15 Given the relatively high probability of urinary tract infections based on symptoms alone and the general safety of antibiotic therapy, empiric treatment of uncomplicated urinary tract infections based on symptoms alone has been found to be safe and cost-effective.16,17 Urinary incontinence frequency during the prior week was assessed by questions that included, "How many times, on average, have you unintentionally leaked some urine with coughing, sneezing, straining, laughing, or lifting?" (stress incontinence) and "How many times, on average, have you unintentionally leaked some urine before you could get to the bathroom?" (urge incontinence). Responses were recorded as times per week.
The effect of random assignment to hormone therapy on urinary tract infections was assessed by comparing the proportions of women reporting none, one, or two or more urinary tract infections at each annual visit, by treatment assignment, according to the intention-to-treat principle. This repeated ordinal outcome measure distinguishes women with sporadic and multiple urinary tract infections. An unadjusted proportional odds model for repeated ordinal measures18,19 was used to test the treatment effect. This model uses generalized estimating equation20,21 methodology to account for correlation between outcome measures for each study participant. As an additional assessment of hormone therapy effectiveness, we compared the proportions of women in each treatment group with one or two or more urinary tract infections in any of the first 4 years of study follow-up. These proportions were compared using an unadjusted proportional odds model for univariate outcomes. In this analysis, the Heart and Estrogen/Progestin Replacement Study cohort would have provided 80% power to detect a protective effect of approximately 22%; slightly smaller protective effects would have been detectable in the primary analysis using repeated measures. The univariate model was also used to assess center-to-center variation; no evidence was found for clustering of outcomes by center or for interactions between treatment assignment and center.
In the prospective cohort analysis, risk factors for urinary tract infections were assessed using adjusted proportional odds models for the same repeated ordinal measure of urinary tract infection frequency in each yearly reporting period. In this analysis, risk factor measurements from baseline or the current annual visit were used to predict the number of urinary tract infections occurring during the following year and reported at the subsequent annual visit. For example, urinary tract infections during the year before the third annual visit were assessed in terms of predictors measured at the second annual visit. This method of analysis potentially captures prospective links between time-dependent covariates updated annually and urinary tract infections that occur in the following year. In contrast to the unadjusted analysis of treatment effects, this analysis of Heart and Estrogen/Progestin Replacement Study as a prospective observational cohort required careful multivariable modeling of potential confounders, as well as possible interactions between risk factors and treatment assignment.
In supplemental analyses, a generalized estimating equation logistic model for repeated binary measures was used to examine whether a history of urinary tract infections in the past year independently predicts urge urinary incontinence during the following year. In addition, generalized estimating equation logistic models were used to examine whether risk factors differentially affected risk for the first and subsequent urinary tract infections in each period.
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RESULTS |
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). Most participants were married (58%), white (89%), and parous (91%). Nearly two thirds of the women were not sexually active in the past 6 months and almost all of those who reported sexual intercourse said the frequency was once a week or less. About 80% reported good or better overall health. In the prior year, 8% reported one urinary tract infection, and 4% had two or more infections. None of these or other baseline characteristics varied by treatment group (Table 1).
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). Overall, using the proportional odds model for repeated ordinal measures, there was a tendency for urinary tract infection frequency to be more common in the hormone-treated group than in the placebo group, but the difference was not statistically significant (OR 1.16, 95% CI 0.99, 1.37, P = .07).
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). Women who reported diabetes with use of insulin had the highest increased risk (81%), and those on oral medications had a 44% increased risk of urinary tract infections. History of childbirth, vaginal itching and dryness, urge incontinence, and poor overall health were also associated with the occurrence of urinary tract infections during the year. When controlling for history of urinary tract infections in the prior year, parity, vaginal itching, poor overall health, diabetes with use of insulin, and urge incontinence remained independent risk factors for incident urinary tract infections. In a supplemental analysis, history of urinary tract infections in the previous year was found to independently predict urge urinary incontinence (OR 1.16, 95% CI 1.04, 1.30, P = .008).
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We found no significant associations with urinary tract infection risk of marital status, years since menopause, sexual intercourse frequency, body mass index, waist/hip ratio, hypertension, myocardial infarction, congestive heart failure, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, and smoking or drinking habits. After controlling for diabetes status in the multivariable analysis, fasting glucose was not a statistically significant predictor of urinary tract infections.
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DISCUSSION |
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We examined risk factors for urinary tract infections in our cohort of postmenopausal women. The risk factors we identified included parity, vaginal itching and dryness, urge incontinence, poor overall health, and diabetes.
Both bacteriuria and urinary tract infections are more common in patients with diabetes than in patients without diabetes.23,24 Among adults with diabetes, women with type 2 diabetes have the highest prevalence of urinary tract infections.25 Although we did not specifically ask participants what type of diabetes they had, most of our participants with diabetes undoubtedly had type 2 diabetes. One hypothesized mechanism of an effect of diabetes on urinary tract infection risk has been elevated glucose levels.26–29 We did not observe an association between glucose level and urinary tract infection risk among women with treated diabetes, but a single blood sugar is an imprecise indicator of diabetic control, so we had little power to observe any association. Our finding that women with diabetes requiring insulin are at greater risk of urinary tract infections than other women with diabetes may reflect a longer duration or more severe diabetes. This can cause peripheral neuropathy, which may lead to uropathies that increase residual volume and bacterial growth.30,31
Although prior studies have identified urinary incontinence as a risk factor for urinary tract infections,8,9,32 the type and frequency of incontinence has not been determined. We found that urge incontinence increased risk of urinary tract infections 51%, whereas stress incontinence was not associated with an increased risk. Interestingly, urinary tract infections have been identified as risk factors for urge incontinence,33 and the causal relationship between urinary tract infections and incontinence may be bidirectional. In a supplemental analysis of the Heart and Estrogen/Progestin Replacement Study data, urinary tract infections were prospectively associated with urge incontinence. Urinary tract infections appear to stimulate bladder detrusor activity and inhibit alpha adrenergic receptors in the urethra, which reduces sphincter pressure and leads to incontinence.34,35 Treatment of urinary tract infections has been shown to improve urge incontinence.34 Further study to determine the causal relationship of urge incontinence and urinary tract infections or to determine if treatment of urge incontinence may prevent or decrease risk of urinary tract infections would be of interest.
Childbirth causes damage to the pelvic supportive structures resulting in cystocele and other types of pelvic organ prolapse.36–38 Prior studies have suggested that cystocele increases postvoid residual volume and decreases urinary flow, thereby contributing to the development of urinary tract infections.8 Therefore, the effect of childbirth on the pelvic floor and lower urinary tract may be the basis for the increased risk.
In our population, urinary tract infection risk increased among women who rated their health as fair or poor, even after adjustment for other risk factors. Other investigators have identified bacteriuria as a marker of underlying illness and increased risk of mortality.39
There is also some evidence that the risk factors for multiple urinary tract infections may differ from those for a single, sporadic urinary tract infection. In particular, the lower risk of multiple urinary tract infections in black women is consistent with a similar result seen among younger women.40 Whether this is attributed to differences in health behaviors, access to care, or an underlying biologic difference is uncertain and deserves further study. Prior studies have demonstrated that black women have higher urethral pressures and pelvic support.41 This suggests a greater ability to prevent retrograde infection from vaginal flora.
Our finding of a history of urinary tract infections in the prior year increasing risk seven- to 18-fold is similar to prior studies in both pre- and postmenopausal women. In one study of women aged 40–65, a history of three or more urinary tract infections any time in their life increases risk of current urinary tract infections almost six-fold; a urinary tract infection in the past 12 months increases risk of current urinary tract infections 14-fold.9 Similarly, among college-aged women, the risk of a second urinary tract infection in the first 6 months after a first urinary tract infection is 24%, exceeding the 17.5% annual incidence of a first urinary tract infection in this age group.1 Clearly, urinary tract infection history is an important determinant of current urinary tract infection risk in pre- and postmenopausal women.
Although sexual intercourse is a strong risk factor among younger women, it was not in our cohort or in one other study of older age groups.9 Sexual intercourse is hypothesized to increase urinary tract infections by moving potential uropathogens into the bladder, by traumatizing periurethral tissues, and by transmitting new infectious agents from the sex partner. In our study, the incidence of urinary tract infections among postmenopausal women varies little by frequency of sexual activity: from 7.7% to 9.2%. Increasing immunity with age is one possible explanation.
Although this study has many strengths, including the large sample size, randomization, and prospective exposure assessment in a cohort followed for 4 years with a good response rate, there are some limitations. First, urinary tract infection was assessed by self-report of a physician diagnosis. It is possible that the women’s recollections were inaccurate, or that other conditions were mistakenly diagnosed as urinary tract infections. We have no reason to believe that these errors occurred more frequently among specific exposure groups, so the impact of any such misclassifications would be to decrease the magnitude of the observed associations. Other limitations include the fact that exposures were assessed only once per year. Urinary tract infection is an acute infection, and it is likely that what happened in the 2 weeks previous to the urinary tract infections is more predictive than a more remote event. We have no measure of the duration of the exposures such as vaginal itching and dryness. In addition, our study subjects were postmenopausal women with heart disease, and it is possible that the findings would be different in healthy women.
In summary, we found oral hormone therapy did not affect incidence of urinary tract infections. The epidemiology of urinary tract infections in postmenopausal women differs from that in premenopausal women. Potentially modifiable risk factors to prevent or decrease risk of urinary tract infection in postmenopausal women include diabetes, urge incontinence, and vaginal dryness and itching.
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Footnotes |
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Received May 14, 2001. Received in revised form August 16, 2001. Accepted August 23, 2001.
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REFERENCES |
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