The Prevalence and Causes of Nocturia

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1 The Prevalence and Causes of Nocturia J. L. H. Ruud Bosch,*, and Jeffrey P. Weiss From the University Medical Center Utrecht, Utrecht, The Netherlands (JLHRB) and SUNY Downstate Medical School, Brooklyn, New York (JPW) Abbreviations and Acronyms BPH benign prostatic hyperplasia BPO benign prostatic obstruction FVC frequency-volume chart ICS International Continence Society LUTS lower urinary tract symptoms NP nocturnal polyuria OAB overactive bladder Submitted for publication October 6, Supplementary material for this article can be obtained by to umcutrecht.nl. * Correspondence: Department of Urology, HP: C04.236, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands (telephone: ; FAX: ; J.L.H.R.Bosch@umcutrecht.nl). Financial interest and/or other relationship with Ferring and GSK. Financial interest and/or other relationship with Pfizer, Ferring, Allergan, Vantia, Astellas and Watson Pharmaceuticals. Editor s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 810 and 811. Purpose: Nocturia is a troubling condition with implications for daytime functioning. However, it often goes unreported. Many prevalence studies exist but differences in populations and definitions of nocturia render assimilation of the data difficult. This review provides an overview of the nocturia prevalence literature. Materials and Methods: A PubMed search was performed to identify articles published in English from 1990 to February 2009 reporting nocturia prevalence in community based populations. Rates reported as overall data, and by age and by gender, were plotted for comparison. Results: A total of 43 relevant articles were identified. Prevalence rates in younger men (20 to 40 years) were 1 or more voids in 11% to 35.2% and 2 or more voids in 2% to 16.6%. Prevalence rates in younger women were 1 or more voids in 20.4% to 43.9% and 2 or more voids in 4.4% to 18%. In older men (older than 70 years) rates were 1 or more void in 68.9% to 93% and 2 or more voids in 29% to 59.3%. In older women rates were 1 or more void in 74.1% to 77.1% and 2 or more voids in 28.3% to 61.5%. Therefore, in practice up to 1 in 5 or 6 younger people consistently wake to void at least twice each night. In some studies younger women appeared more likely to be affected than men. Up to 60% of older people void 2 or more times nightly. Conclusions: Nocturia is common across populations. It is most prevalent in older people but it also affects a significant proportion of younger individuals. Clinicians should be alert to the possibility that nocturia may impact the sleep, quality of life and overall health of their patients. Since the condition is highly multifactorial, frequency-volume charts are invaluable tools for the diagnosis of underlying factors and for treatment selection. Key Words: nocturia, prevalence, epidemiology IN 2002 the ICS proposed the first standardization of nocturia terminology, marking a new era in the field of urological research and in particular in the approach to the management of LUTS. 1 While many factors may contribute to nocturia the report clearly recognized that nocturia, which had long been overlooked or considered part of an array of symptoms of some other primary disorder, can, in fact, be a clinical entity in its own right. According to the ICS report nocturia is the complaint that the individual has to wake at night 1 or more times to void. Each void is preceded and followed by sleep. Therefore, those who wake up to void just once during the night are considered to have nocturia. However, while this definition offers clarity and consistency in terminology, it does not impose judgment regarding when nocturia becomes clinically significant, and S /13/ /0 THE JOURNAL OF UROLOGY Vol. 189, S86-S92, January by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A. Please cite this article as J Urol 2013;189: S86-S92. DOI:

2 PREVALENCE AND CAUSES OF NOCTURIA S87 worthy of full diagnostic investigation and treatment. However, empirical evidence suggests that most people with less than 2 voids nightly generally experience only minimal bother from the condition. However, when 2, 3 or more voids nightly are experienced on a regular basis this is likely to have more serious consequences for the patient. 2,3 Therefore, it seems that when 2 or more voids per night are experienced the experience of nocturia shifts from a perception of the condition as a minor inconvenience to a significantly bothersome and clinically meaningful condition. Indeed among LUTS, which encompass voiding, post-voiding and storage symptoms (including nocturia), nocturia is consistently reported to be one of the most bothersome symptoms by men as well as women. Of course individuals vary, and some people with only 1 void nightly may find this troublesome while some with severe nocturia appear not to be highly bothered. The detrimental impact of nocturia is caused by the associated sleep fragmentation experienced by patients on a regular basis, and some studies suggest that the degree of bother associated with nocturia is significantly related to sleep status rather than nocturnal voiding frequency per se. 4 There are a wide range of negative sequelae of nocturia and poor sleep including reduced quality of life, mood disturbance, reduced productivity at work, poorer overall health, and increased falls and fractures. 5 More studies in this area will help to confirm, elucidate and add to such findings. Despite the bother experienced by patients, nocturia is an underreported condition and, therefore, the true extent of the problem in the population may be underestimated. A study of women with urinary incontinence and/or OAB revealed that although the majority of women rated their urinary symptoms, including nocturia, as moderately or extremely bothersome, more than half had not consulted a doctor. 6 More than a third of the women (37%) indicated that they would prefer their health care provider to initiate discussions about urinary symptoms. Such studies highlight the fact that people may be embarrassed or reluctant to discuss symptoms such as nocturia, they may not realize that treatment is available and that they perceive nocturia as something that must be accepted with aging. Therefore, these factors may represent barriers to the identification of patients for whom investigation regarding the etiology and corresponding treatment of nocturia would be appropriate. Several reports of nocturia prevalence exist in the literature. These articles may give a more reliable estimate of the rate of the condition in the population than can be gained in clinical practice since the studies involve direct questioning regarding symptoms which may not otherwise be reported. Nonetheless prevalence estimates vary, and are affected by the population studied, the age range considered and the definition of nocturia used. This summary of the results of prevalence studies from around the world provides a comparative overview of findings to date. METHODS We performed a simple PubMed search for articles written in English, published from 1990 until February 2009, reporting nocturia prevalence rates in the population with the search terms nocturia prevalence. Therefore, studies referring to nighttime voiding frequency or LUTS but not nocturia may have been missed. However, the intention was not to perform an exhaustive search but rather to identify a representative sample of articles from which to gain an impression of the range of prevalence estimates in the literature. Only studies with rates that were stated as percentages in the text, as opposed to being presented in figures without stating exact values, were included in the review. To give a visual representation of the rates reported in the various studies these were plotted in figures. Where rates were reported for an age range the midpoint of the range was used to plot the prevalence reported for the age group except when the range was indefinite (eg 70 years or older), in which case rates were plotted at the minimum age of the range. When rates for 1 or more, or 2 or more voids per night were not presented explicitly but could be calculated (eg from data for 1 void, 2 voids and 3 or more voids), this was done and these results were presented to allow comparability across studies. RESULTS We identified 45 relevant studies reporting the prevalence of nocturia in a population sample. The results of 1 of these studies were also reported in a followup report, and results of another pertained to the same sample that had been included in an earlier article. Removing these 2 articles left 43 that presented overall rates of nocturia in the population and/or rates within particular age groups. 2,3,7 47 One study drawing its sample from a clinical rather than general population was included in the analysis because the inclusion criteria stated that participants had no subjective complaints concerning urination. 16 Rates of nocturia in this sample were not exceptional, although the definition used (occasionally or always having nocturia) was not the same in any other studies and, therefore, straightforward comparison is not possible. Several studies concentrated on only 1 gender while others presented results for men and women. As shown in figure 1 all studies showed a tendency for nocturia to increase with age for both genders. The figures must not be taken as precise reflections of the prevalence for a specific age since the rates have been plotted in the midpoint of age categories reported in the studies. However, from

3 S88 PREVALENCE AND CAUSES OF NOCTURIA men in their 20s and 30s, 11% to 35.2% reported at least 1 void per night while 2% to 16.6% reported 2 or more voids nightly. Of men in their 70s and 80s, 68.9% to 93% reported at least 1 void per night while 29% to 59.3% reported at least 2 voids per night (fig. 1, B). As expected, overall prevalence rates for full samples investigated demonstrate that more severe nocturia is less common than less severe nocturia (fig. 2). Note that wide variations in the prevalence are to be expected since the age of the samples differs considerably, with some looking exclusively at specific age groups. Furthermore, overall rates may be misleading. For example, Zhang et al report a prevalence of only 9% in their random sample of Fuzhou Chinese women 20 years old or older. 37 However, 84% of their sample was in fact younger than 50 years and, therefore, the relatively low overall prevalence may be influenced by the predominance of younger participants. Figure 1. Prevalence of nocturia across age groups in women (A), men (B), and men and women (combined sample, C). Plotted value for women 55 to 74 years old with 2 or more voids from van Dijk et al differs from published value due to erratum in original publication. 3 Additional percentage data supplementary to those published were available for Blanker et al due to involvement of 1 author of current review in original study. 9 our graphical representations 20.4% to 43.9% of women in their 20s and 30s reported experiencing at least 1 void per night while 4.4% to 18% of women in this age category reported 2 or more voids nightly. Of women in their 70s and 80s, 74.1% to 77.1% reported 1 or more voids per night while 28.3% to 61.5% reported 2 or more voids nightly (fig. 1, A). Of DISCUSSION Prevalence of Nocturia The results of this literature review show that nocturia is present in a significant proportion of all populations studied, and across nationalities, gender and age groups. In practical terms up to 1 in 5 or 6 younger people consistently wake to void at least twice each night on average. Voiding at least once nightly tended to be reported more frequently in younger women than in younger men (20.4% to 43.9% and 11% to 35.2%, respectively), but was equally common or more so in men in older age groups. 3,12,26,31,39 In particular Tikkinen et al observed that young women (18 to 29 years old) are more than 10 times more likely to have nocturia than young men (prevalence ratio 11.5) in the Finnish population studied. 31 However, some studies report a similar rate of nocturia in men and women across all age groups. 2,34,36 The reasons for the possible increased prevalence of nocturia in younger women vs men, and/or factors relating to study design which may lead to these varied findings, are subjects for further investigation. It may be that women experience greater fragmentation of sleep due to other causes (eg child care at night) or that they are simply more prone to insomnia than men and that these issues affect the reporting of nocturia. It is interesting to note that the studies that do indicate a gender difference in younger people come from several different countries and continents (Europe, Asia, Australia and Canada). Therefore, the underlying reasons for this observation are unlikely to be confined to a specific country or culture. The majority of older men and women experience at least 1 void per night and on average up to twothirds experience 2 or more voids per night. When

4 PREVALENCE AND CAUSES OF NOCTURIA S89 data from the various studies are collated a pattern emerges whereby around half of the population experiences at least 1 void per night from the age of 50 to 60 years while approximately 25% of the population experiences 2 or more voids nightly by their early 60s. Severity continues to increase with age. Figure 2. Overall prevalence of nocturia reported for full age range studied by number of nocturia episodes per night in women (A), men (B), and men and women (combined sample, C). Causes of Nocturia and Their Prevalence We have established that nocturia is a condition that affects a substantial proportion of the adult population including younger people. The bother experienced by patients with nocturia as well as the impact on quality of life, daytime functioning and overall health can be severe. Therefore, it is important for the causes of nocturia to be diagnosed accurately so that effective treatment can be given as necessary. Nocturia is a multifactorial condition with many possible contributing etiological factors. Patients may be affected by 1 or several of these factors, and it is crucial that none are overlooked if a significant and clinically meaningful reduction in nighttime voids is sought by the patient. The possible causes of nocturia have been reviewed in detail elsewhere and are summarized in the Appendix. 1 While an association between these risk factors and nocturia has been established, estimates of the proportion of patients with nocturia who are in fact affected by each underlying factor are less common in the literature. In a study by Bing et al patients with nocturia and controls between 60 and 80 years old were compared based on various aspects of health including hypertension, heart disease, diabetes mellitus, lower limb edema, neurological symptoms, lung disease and urinary incontinence. 48 No significant difference in the prevalence of concomitant diseases/ symptoms was found between the groups. In their study of data from a Japanese health screening program Yoshimura et al found that although diabetes mellitus and hypertension were significantly associated with nocturia on multivariate analysis, the prevalence in patients with nocturia was only 2.0% and 10% greater, respectively, than in the overall sample (6.2% vs 4.2% for diabetes mellitus and 34% vs 24% for hypertension). 34 Therefore, although the association is clear, it may be crudely extrapolated that these conditions are relatively modestly increased in patients presenting with nocturia compared with levels in the background population. The majority of patients with nocturia in the study were not affected by these conditions. Therefore, the key causes of nocturia for most patients encountered in clinical practice are likely related to other factors. The diagnosis of nocturia and specific urological causes is still a somewhat misunderstood field. OAB is associated with nocturia by the nature of its ICS definition. 1 Blanker et al showed BPH was a significant determinant of nocturia (more than 2 voids) in a multivariate analysis. 9 However, OAB and BPO are primarily characterized by accompanying daytime symptoms (eg urgency, hesitancy or small

5 S90 PREVALENCE AND CAUSES OF NOCTURIA voided volumes), and patients with pure OAB and BPO have a normal urinary output volume. A frequent contributor to nocturia is nocturnal polyuria. NP is an overproduction of urine at night (defined as a urinary output greater than 20% of the daily total in young individuals and greater than 33% in older individuals), believed to be due to inadequate secretion of the antidiuretic hormone arginine vasopressin at night. A state of altered hemodynamics is an important factor in the etiology of NP. 1 Theoretically sleep deprivation can change hemodynamics and thereby increase nighttime urine production, adding to the complexity of the relationship between sleep and nocturia. Nocturia can be caused solely by NP, or by a combination of NP and OAB and/or BPO. However, NP is often missed during the evaluation and diagnosis of nocturia despite the fact that it is perhaps the most common factor underlying nocturia. Even in men with LUTS suggestive of BPO as many as 95% have been reported to have NP. 49 Therefore, failure to treat NP will fail to achieve a clinically significant improvement in nocturia for these patients. In a recent study in Finland the authors investigated factors associated with nocturia and their impact at the population level including BPH. 50 No single correlate accounted for more than half of the cases of nocturia, again demonstrating the multifactorial etiology of the condition. The correlates with the greatest influence at the population level were urgency, BPH and snoring for men, and being overweight, urgency and snoring for women. Due to the nature of the study which was based on a questionnaire mailing, NP itself was not specifically assessed. Since no single factor was overwhelmingly responsible for the population burden of nocturia it is possible, as suggested by studies of NP prevalence in patients with nocturia, 49 that an overproduction of urine at night may have been a contributing factor in a significant proportion of cases. Given the wide array of possible contributors to nocturia a key diagnostic tool is the FVC, in which patients record the volume and timing of daytime and nighttime voids for 1 to 3 days. These data allow clinicians to interpret the voiding pattern, and make informed judgments regarding the etiology of nocturia and the possible involvement of 1 or more contributing factors. Patients may have a reduced voided volume (indicating a reduced capacity of the bladder to store urine), excessive urine production during the day and night (indicating 24-hour polyuria) or excessive urine production specifically at night (indicating NP). There can be a marked discrepancy between nocturnal voiding data obtained using FVCs and data from subjective questionnaires such as the International Prostate Symptom Score. 9 Therefore, it is our recommendation that FVCs should be used routinely in clinical practice to enable the accurate diagnosis and appropriate treatment of nocturia. CONCLUSIONS While reported nocturia prevalence rates vary considerably, even when factors such as definitions of nocturia and age of the sample population are consistent, there are some findings which are reported repeatedly across studies and countries. Specifically nocturia is a common condition. Although it increases with age, a substantial proportion of younger adults are also affected. With the more stringent but more clinically meaningful cutoff of 2 or more voids per night nocturia is experienced by up to approximately 15% to 20% of young adults. The negative impact of sleep fragmentation caused by nocturia may be particularly difficult for these younger patients because they are more likely to have active lifestyles and demanding work schedules. All studies demonstrated a marked increase in nocturia with age and several reported prevalence rates of 2 or more voids approaching or exceeding 50% in older populations, highlighting the pervasive nature of this underreported condition. Clinicians should maintain awareness of the possibility that their patients are affected by this condition and of the likelihood that patients are reluctant to discuss it. Proactive questioning regarding nocturia, and LUTS in general, may help to elicit reports from patients who are experiencing negative consequences of nighttime voiding and to allow treatment to be offered where appropriate. There are many possible causes of nocturia. However, in patients affected by the rarer and/or more immediately life threatening contributors such as heart failure and diabetes mellitus, nighttime voiding is unlikely to be the primary complaint. Once these conditions have been ruled out nocturia is often confused with LUTS and assumed to be a symptom of OAB or BPO. However, NP is present in up to 83% of the general population with nocturia and, as such, clinicians should be alert to the fact that this overproduction of urine at night may be a key contributory factor in their patients, even those with an OAB or BPO diagnosis. NP can be identified easily with the routine use of FVCs, which also provide a reasonable indication of the patient functional bladder capacity. ACKNOWLEDGMENTS Editorial assistance was provided by Caroline Loat, ScopeMedical Ltd and supported by Ferring Pharmaceuticals.

6 PREVALENCE AND CAUSES OF NOCTURIA S91 APPENDIX Potential Factors Underlying Nocturia 1 Urological evaluation reveals: Reduced nocturnal bladder capacity 24-Hour polyuria Nocturnal polyuria ICS definition: Urine production within normal limits; increased frequency, small voided volumes (clear definition lacking) especially during sleep time 24-Hour urinary output exceeding 40 ml/kg body weight Possible etiology: OAB Poorly controlled diabetes mellitus (Type 1 or Type 2) Nocturnal urine volume greater than 20% to 33% of total 24-hour urinary volume (dependent on age) Excessive evening fluid/caffeine intake Bladder outlet obstruction, including BPH/BPO Diabetes insipidus Impaired circadian rhythm of arginine vasopressin secretion Interstitial cystitis Hypercalcemia Renal insufficiency Urinary tract infection Polydipsia Congestive heart failure Bladder hypersensitivity Diuretic use Calculi Estrogen deficiency Cancer Sleep apnea Neurogenic detrusor overactivity (eg multiple Venous insufficiency sclerosis) Sleep problems, eg insomnia, restless leg syndrome Edema Hypoalbuminemia REFERENCES 1. van Kerrebroeck P, Abrams P, Chaikin D et al: The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. 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