The Epidemiology of UI and its Subtypes: Insights into Current Understanding and Future

Directions

Vatche A. Minassian, MD, MPHDirector of Urogynecology

Brigham and Women’s HospitalAssociate Professor

Harvard Medical School

DISCLOSURE

I have no financial relationship with a commercial entity producing health-care related products and/or services.

Objectives

• Define urinary incontinence (UI) and its subtypes

• Describe what is known and unknown about the epidemiology of UI, risk factors, and UI health care delivery

• Present available UI data sets or data sources important to understand UI natural history

• Discuss current and future research ideas that help decipher the “known unknowns”

Knowns and Unknowns

• “[T]here are known knowns; there are things we know we know.We also know there are known unknowns; that is to say we know there are some things we do not know.But there are also unknown unknowns – the ones we don't know we don't know.”

Former United States Secretary of Defense Donald Rumsfeld

Knowns and Unknowns(Faryumadi)

• One who knows and knows that he knows...– His horse of wisdom will reach the skies.

• One who knows, but doesn't know that he knows...– He is fast asleep, so you should wake him up!

• One who doesn't know, but knows that he doesn't know...– His limping mule will eventually get him home.

• One who doesn't know and doesn't know that he doesn't know...– He will be eternally lost in his hopeless oblivion!

Ibn Yamin Faryumadi: Persian Poet (1286-1368)

Why is Research Important?

• Is it to produce scholarly work that gets published as a manuscript in a prestigious journal?

General Medicine Journals

(JAMA)

(NEJM)

Why is Research Important?

• …or is it to publish in a journal that is known more by its color than its name?

General OB/GYN Journals

AJOG

(The Gray

journal)

Obstetrics &

Gynecology

(The Green

Journal)

(The Maroon

journal)

IUJ

(The Purple

journal)

Journal of Pelvic

Medicine &

Surgery

(The Gold

journal)

Urogynecology Journals

The Real Question Is:

• Who is reading those journals anyway?

Journals and Manuscripts

• Medical student: who reads the manuscripts but has

a hard time understanding them

• Intern: who uses the journal as a pillow

• Resident: who wants to read but eats instead

• Chief resident: who skips the manuscripts to the

classified ads

• Private physician: who does not buy the journal

Journals and Manuscripts

• Junior faculty: who reads the abstracts only

• Senior faculty: who makes the resident

summarize the manuscripts at journal club

• Chairman: who reads the titles only

• Dean: who reads the manuscripts but has a hard

time understanding them

Adapted from James Scott, MD Editor, Obstet Gynecol

2002 AUGS meeting in San Fransisco

“If your job is to shovel, and all

you see ahead is dirt, it’s time to change jobs.”

Is the situation that bad?

In reality,

• The picture is not that gloomy

• Most of us (including myself) conduct research for the sake of:– Advancing science and knowledge

– Improving patient care

– Getting a raise and academic promotion

– Achieving excellence and recognition

– Just for the fun of it!

Definition of UI

• International Continence Society

–1979: involuntary urine loss, social or

hygienic problem, objectively demonstrable

–2002: the complaint of any involuntary

leakage of urine

–2010: same definition as in 2002

Bates P et al. J Urol 1979;121:551-554.Abrams P et al. Neurol Urodyn 2002;21:167-178

Haylen BT et al. Neurol Urodyn. 2010; 29(1):4-20.

Definition of UI(Complexities)

• 1st definition: restrictive (false -)

• 2nd definition: inclusive (false +)

• Duration not addressed

• Severity and continuum of disease

• Cut-off for clinical significance

Classification of incontinence

• Stress urinary incontinence– The complaint of involuntary leakage on effort or

exertion, or on sneezing or coughing.

• Urgency urinary incontinence– The complaint of involuntary leakage accompanied

by or immediately preceded by urgency

• Mixed urinary incontinence– Both stress and urgency incontinence

Haylen BT et al. Neurol Urodyn. 2010;29(1):4-20.

Prevalence studies

• Urinary Incontinence: worldwide problem

• Prevalence in women increases with age

• Wide range in prevalence rates (2-58%)

• Differences in definition, populations, survey

type, response rate, age, availability of health-

care and others

• Prevalence varies by UI subtype

Hunskaar S et al. Int Urogynecol J Pelvic Floor Dysfunct 2000;11:301-19.

Prevalence of Significant UI

0

5

10

15

20

25

30

35

40

5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

Age range (years)

Pre

va

len

ce

(%

)

Minimum Maximum Median

Minassian VA et al. Int J Gynecol Obstet 2003;82:327-338

Prevalence of Urinary Incontinence

14%

32%

4%

50% stress

urge

mixed

other

Minassian VA et al. Int J Gynecol Obstet 2003;82:327-338

UI Risk Factors

Risk Factor Urinary Incontinence Subtype

Stress UI Urgency UI Mixed UI

Age

<50

>=50

++

No effect

+

++

+

++

Race (white = ref)

Black

Hispanic

--

-

++

-

-

--

Parity ++ No effect +

Obesity ++ ++ ++

Diabetes ++ ++ +

COPD / Smoking ++ + ++

Surgery for SUI -- + -

Data Source - 1

• Review of the literature

• Meta-analysis / systematic review–www.pubmed.gov

–www.cochrane.org

–Society reviews and opinions (AUGS, AUA, SUFU, other)

– International Consultation on Incontinence (ICI)

NHANES

Fig. 1. Prevalence of Stress Urinary Incontinence

by Age and Severity

0

5

10

15

20

25

30

35

40

45

50

Age

Pre

vale

nce (

%)

Mild

Moderate

Severe

Mild 8.6 14.7 20 15.2 9.8 8.1 6.6

Moderate 3.3 5.8 11.5 14.8 11.9 11.9 9.9

Severe 4.7 6.8 11 14.1 9.5 9.1 6.9

20-29 30-39 40-49 50-59 60-69 70-79 80+

Minassian VA et al. Obstetrics and Gynecology 2008;111(2 part 1):324-331.

NHANES

Fig. 2. Prevalence of Urge Urinary Incontinence

by Age and Severity

0

5

10

15

20

25

30

Age

Pre

vale

nce (

%)

Mild

Moderate

Severe

Mild 5.3 6.5 9 9.4 4.8 9.2 5.3

Moderate 2.3 2.3 5.3 5.1 7.7 9.5 10.2

Severe 1 1.2 4 2.7 4.5 4.2 9.9

20-29 30-39 40-49 50-59 60-69 70-79 80+

Minassian VA et al. Obstetrics and Gynecology 2008;111(2 part 1):324-331.

NHANES

Fig. 3. Prevalence of Mixed Urinary Incontinence

by Age and Severity

0

5

10

15

20

25

30

35

Age

Pre

vale

nce (

%)

Mild

Moderate

Severe

Mild 1 2.6 2.9 2.5 1.4 0.74 2.1

Moderate 1.3 2.1 5.2 6.4 6.3 7.4 6.2

Severe 0.6 2.4 5 8.1 14.3 16.2 21.1

20-29 30-39 40-49 50-59 60-69 70-79 80+

Minassian VA et al. Obstetrics and Gynecology 2008;111(2 part 1):324-331.

NHANES

• Key findings:

–Stress UI: Most common subtype

–Urgency UI: Least common subtype

–Mixed UI: Most severe subtype and most common in the elderly

Data Source - 2

• National Health and Nutrition Examination Survey (NHANES):– National survey of a representative sample of the

U.S. population

– Home interview and health examination

– Questions on health status, disease history, and diet.

– Funded by the Center of Disease Control, releases public use data updates every two years

– https://www.cdc.gov/nchs/nhanes/index.htm

Natural History of SUI, UUI, and MUI

0

5

10

15

20

25

30

20 25 30 35 40 45 50 55 60 65 70 75 80

Age group

Pre

va

len

ce

(%

)

SUI

UUI

MUI

Pooled estimates of several population-based studies including Hannestad, Hunskaar, Melville, and Minassian.

An Epidemiologic Paradox

• Prevalence of:– Stress UI: 13%– Urgency UI: 5%– Mixed (Stress AND Urgency) UI: 11%

• Assuming that pure SUI and pure UUI are independent (mutually exclusive):

– Expected (E) co-occurrence (MUI) is [(13+11)% * (5+11)%] = 3.8% versus an observed (O) value = 11%

– The O/E ratio (11/3.8) indicates that the prevalence of MUI is about 3 times the expected value

ExposureBiologically

Effective

Dose

Early

Biological

Effect

Internal

Dose

Altered

Structure

& Function

Clinical

Disease

ExposurePersistent or

chronic UIRare UI Urgency UI

Genetic

modifiers

Genetic

modifiers

Genetic

modifiers

Genetic

modifiers

ParityIncreased

weight

Diabetes,

smoking

Exposure

Factors

Episodic UI

Natural history of UI

Years

Mixed UI

Stress UI

Dynamics of UI SubtypesProposed conceptual model

λ = transition rates from one incontinence subtype to the other; or remission from a UI subtype to no UI

No UI Mixed UI

Stress UI

Urgency UI

Research Plan to Address this Paradox

• Three hypotheses:

– Liability Model

– Severity Model

–Risk Factor Model

Minassian VA, Stewart WF, Hirsch A. Int Urogynecol J. 2008; 19:1429-1440

Liability Model

• Mixed UI occurs more often than expected when:

– Presence of one UI subtype increases liability of the other.

• Likelihood of new onset SUI or UUI is higher if you have one or the other condition than if you have neither.

– UI Remission rates are lower when 2 subtypes (UUI and SUI) are present than if either occurs alone.

– This model posits that the net effect of UI onset, progression and remission favor accumulation of mixed UI cases over time.

Data Source - 3

• Develop your own data-set to answer your question of interest:

– Generally requires funding, time, support staff, and other resources

– Funding requires evidence of previous work or preliminary data

– Funding can be sought at the institution you practice, partnership with industry, NIH, or other sources

Epidemiologic Study (GLOBE-UI)

• Natural History of UI Study (2009-2013)

– Second generation Longitudinal study

– Partnered with industry; received an NIH R01 grant

– Survey sent to 10,000+ community dwelling women

– Follow-up q 6 months for a total of 4 years

– Total of 9 waves of surveys

– Nested case-control and digital diary study

– Close to 7,000 responded to at least one survey

Minassian: GLOBE-UI; NIDDK, NIH. RO1 DK082551

Longitudinal Study

Longitudinal Study Data Collection Schedule

Date Population

Sample1

Bladder Health Questionnaire Phone interview

(Incident Cases)4-week recall

Questions

6-month recall

Questions

Lifetime History

March 2008

(24 month BHQ)

Current X X X

New

July 2009 Current X X X X

New X X X

January 2010 Current & New X X X

July 2010 Current & New X X X

January 2011 Current & New X X X

July 2011 Current & New X X X

January 2012 Current & New X X X

July 2012 Current & New X X X

January 2013 Current & New X X X

July 2013 Current & New X X X

Also includes a nested case control and a digital diary study

Mixed

UI

Stress

UI

Urgency

UI

No UI

Time

Dynamics of UI subtypesRefined conceptual model

• Transition from SUI or UUI to MUI is higher than vice versa

• Remission from MUI is lower than remission from either SUI or UUI

• SUI transition to UUI is higher than UUI to SUI

• Progression model of UI:o SUI may be an early stage

followed by an intermediate UUI stage

o MUI may represent a more advanced UI stage

Data Source – 4a

• Compare your data with other data-sets with UI specific questions:–HRS (Health and Retirement Study):

• http://hrsonline.isr.umich.edu/

• 50+ yo Americans• In-person, biennial interviews since 1992• Publicly available database• Oversamples Black and Hispanic subjects,

allowing analysis of minorities

Dynamics of UI by Subtype

• Using HRS data, Komesu studied progression of UI by subtype

• Over a 2-year period:

– Remission of: MUI (25%); UUI / SUI (about 35%)

– Persistence of: MUI (50%); UUI / SUI (about 33%)

• Put together, these data are consistent with our natural history progression model

Komesu YM, Schrader RM, Ketai LH, Rogers RG. Int Urogynecol J 2016; 27:763-772

Data Source – 4b

• Other similar longitudinal data sources– SWAN (Study of Women’ Health across the

Nation): • http://www.swanstudy.org/• Sponsored by National Institute of Aging• 3,302 women 40+ followed since 1994• Across 7 different research centers in 6

different states• Participants represent 5 racial/ethnic groups

Waetjen LE, Liao S et al. Am J Epidemiol. 2007 Feb 1;165(3):309-318

Iceberg of UI HealthCare Delivery

Percent respondents of sample of women 40+ receiving the Bladder Health Survey from a population of primary care patients

P1 = 47% (3,316/7,059)

Prevalence of UI based on respondents (N= 3,221) to the initial baseline survey

P2 = 41% (1,366/3,316)

Proportion of women with UI seeking care (i.e., with a UI ICD-9 diagnosis)

P3 = 25% (339/1,366)

Percent women with UI receiving care (all clinics)

P4 = 23% (313/1,366)

Percent women with UI at

specialty care

P5 = 12% (164/1,366)

Prevalence of UI

• Prevalence of any UI in women over 40: 1,326/3,221 (41%):

– 75% have UI of 2 years duration or longer

– 75% have moderate or severe UI

– Only 25% sought care

– 12% were seen by a specialist

Minassian VA, Yan X, Lichtenfeld MJ, Sun H, Stewart WF. Int Urogynecol J. 2012; 23:1087-93

Questions

• If urinary incontinence is so prevalent, why do we not pay more attention to it?

• Why is it that only a small fraction of women with UI seek or receive care?

• Why is it important to better understand urinary incontinence?

Lack of Consensus

A gynecologist, urologist, and colorectal surgeon quarrel with each other while ignoring the common ground they all stand on

Lack of Priority

National health interview survey (NHIS)

Prevalence of UI: 30-40%

Knowledge and education

Patient attitudes

• “not life-threatening”

• “normal aging process”

• “? presence of effective treatment”

• “getting used to it”

• “family doctor never asked about leakage”

• “healthcare too expensive”

Aging of population

Aging of population

http://www.census.gov/statab/www

Impact of UI

• Effect on Individual and Societal Health:

– Isolation, suffering, anger, and embarrassment

– Lower SF-36 scores and poorer sleep

– Higher depression scores

– Interference with marital and sexual life

– Increased prevalence of other co-morbidities

– Billions in cost to the economy

– Increased societal burden for years to come

Stewart WF et al. World J Urol 2003:20;327-336Townsend MK, Minassian VA et al. Int Urogynecol J. 2014;25:823-9Minassian, VA, Devore et al. Obstet Gynecol. 2013;121:1083-1090

Data Source – 5• Work (ing) with others with large longitudinal

data-sets with UI specific questions:–NHS and NHS II (Nurses Health Study):

• http://www.nurseshealthstudy.org/• NHS initiated in 1976• 121,700 female nurses, aged 30 to 55 years• Questionnaire on medical history and lifestyle

every two years. • Questions about UI were added on the

questionnaires since 2000, 2002, 2004, 2006, and 2008

• Follow-up rate is approximately 90%.

Where Do We Go From Here?A. Early Detection of Clinically Significant UI

• Develop prognostic tools to identify at-risk women of clinically significant UI within the continuum of disease:– Longitudinal studies with sequential surveys over time – Cross-sectional surveys are insufficient to study UI natural hx

• Develop surveillance in adolescence / young women to study mitigators / risk factors that long predate onset of adult UI – Early stages, women may go from periods of UI activity to inactivity – Over time, they progress, remit, or transition – As disease severity increases, UI is more likely to persist within a specific

UI subtype.

• Distinguish early vs late stage disease to help better deploy appropriate preventive versus treatment strategies.

Where Do We Go From Here?

B. The Enigma of Mixed UI – (Diagnosis)

• Little is known about how MUI develops– Transition from pure SUI or UUI to MUI– Transition directly from continence to new onset MUI

• Exploring pathways that lead to MUI will result in a better understanding of SUI, and importantly UUI, which remains largely idiopathic.

• Future research to develop algorithms with various targeted interventions appropriate for the different MUI phenotypes.

Where do We Go From Here?

C. The Enigma of Mixed UI – (Treatment)

• Not all women with MUI respond to the same treatments

• We hypothesize the presence of 3 treatment algorithms:

– Traditionalists recommend least invasive intervention: e.g., P.T. produces varying degrees of improvement in women with MUI

– Purists favor treating most bothersome UI subtype first

– Interventionalists promote most aggressive intervention: e.g. TVT / Burch treat SUI, and may improve UUI symptoms in many women with MUI

– Each approach has some merit and may play a role in a specific subset of women with MUI

– More research is needed to address various treatment choices

New Frontiers of UI Research

• Epigenetics:

– UI is the product, in part, of genetic predisposition

– Evidence is still limited or inconsistent

– Rigorous familial aggregation studies are important

– Genome-wide association studies (GWAS) are needed to study UI and identify genetic loci associated with UI subtypes

– Early indication of some UI loci by GWAS

New Frontiers of UI Research

• Urinary microbiomes (and proteomics) – Common microbes in the urine: lactobacillus,

gardnerella, and enterobacteriaceae– Altered microbiome in women:

• associated with UUI (↑ gardnerella and ↓ lactobacillus species)

• associated with lower responsiveness to treatment

– Early suggestion of an association of altered urinary protein with stress UI

– What does a healthy bladder mean with regards to the microbial flora?

– Variations by age, race, BMI, menopause, lifestyle

Data Source – 6

• Helpful data sources to research these and other epidemiologic ideas:– Academic institutions with UI cohorts / databases

• Kaiser (CA); Beaumont (MI); Brigham (MA); Others

– Private / public partnerships• BACH (https://www.niddkrepository.org/studies/bach)• www.neriscience.com/Epidemiology

– Women’s Health Initiative (WHI); GARNET substudy• https://www.whi.org/

– Studies performed by NIH-sponsored networks• PFDN (https://pfdnetwork.azurewebsites.net/)• PLUS (https://plusconsortium.umn.edu/)• Other

Concluding Thoughts

• Epidemiology has advanced our understanding of the natural history of UI, differentiation of subtype, etiology, and treatment modalities

• Many questions remain unanswered

• The complexity of the bladder is in its simplicity. – The key symptom in bladder control problems is urine loss

– There are many underlying causes that lead to UI

• Using epidemiologic tools, our mission should be to decipher what remains unknown in UI, and help answer complex etiologic questions on UI subtypes.