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Recurrent Vulvovaginal Candidiasis

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DOI: 10.1016/j.annepidem.2017.08.010

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 Annals of Epidemiology 27 (2017) 575e582

Contents lists available at ScienceDirect

Annals of Epidemiology
journalhomepage:www.annalsofepidemiology.org

Review article

Recurrent vulvovaginal candidiasis

a a b
Freida Blostein , Elizabeth Levin-Sparenberg MPH, PhD , Julian Wagner PhD , Betsy
a,
Foxman PhD *
aCenter for Molecular and Clinical Epidemiology, University of Michigan, School of Public Health, Ann Arbor
b Independent, Lausanne, Switzerland

article info abstract

Article history: Purpose: Recurrent vulvovaginal candidiasis (RVVC), multiple episodes of vulvovaginal candidiasis (VVC; vaginal yeast
Received 3 April 2017 infection) within a 12-month period, adversely affects quality of life, mental health, and sexual activity. Diagnosis is not
Accepted 4 August 2017 straightforward, as VVC is defined by the combination of often nonspecific vaginal symptoms and the presence of yeastdwhich
Available online 15 August 2017
is a common vaginal commensal. Estimating the incidence and prevalence is challenging: most VVC is diagnosed and treated
empirically, the availability for purchase of effective therapies over the counter enables self-diagnosis and treatment, and the
Keywords:
duration of the relatively benign VVC symptoms is short, introducing errors into any estimates relying on medical records or
Vulvovaginal candidiasis
patient recall.
Recurrent
Prevalence
Incidence Methods: We evaluate current estimates of VVC and RVVC and provide new prevalence estimates using data from a 2011
Diagnosis seven-country (n ¼ 7345) internet panel survey on VVC conducted by Ipsos Health (https://www.ipsos.com/en). We also
evaluate information on VVC-associated visits using the National Ambulatory Medical Care Survey.

Results: The estimated probability of VVC by age 50 varied widely by country (from 23% to 49%, mean 39%), as did the
estimated probability of RVVC after VVC (from 14% to 28%, mean 23%).
Conclusions: However estimated, the probability of RVVC was high suggesting RVVC is a common condition.

2017 Elsevier Inc. All rights reserved.

Introduction The availability of over-the-counter treatment, challenges of diagnosis,

Vulvovaginal candidiasis (VVC) affects as many as one of every two
women during their life but is perceived as a common or nuisance condition
because it is easily treated, often with medicines available over the counter
[1e5]. However, on a population scale VVC’s impact is large, costing an
estimated $2.84 billion in the United States alone (adjusted to 2017 dollars
from [6]). Most women will experience only one or two episodes of VVC, but
there is a large, albeit poorly defined, subset that experiences multiple
recurrences [6e9]. Recurrent vulvovaginal candidiasis (RVVC) adversely
affects quality of life, mental health, and sexual activity [10e12]. Diagnosis is
not straightforward, as it is defined by the combination of often nonspecific
vaginal symptoms and the pres-ence of yeastdwhich is a common vaginal
commensal [2, 13]. In clinical practice, VVC and RVVC are usually treated
based solely on signs and symptoms.
Drs. Wagner and Foxman have consulted for NovaDigm Therapeutics.
* Corresponding author. Department of Epidemiology, 1415 Washington Heights, Ann Arbor,
MI 48109-2029.
E-mail address: bfoxman@umich.edu (B. Foxman).
and perceived benign nature, pose significant challenges for accurately
estimating the occurrence and risk of recurrence. In this review, we evaluate
current estimates of VVC and RVVC, pro-vide new estimates using data from
the National Ambulatory Medical Care Survey (NAMCS) and a 2011
multicountry internet panel survey on VVC conducted by Ipsos Health
(https://www. ipsos.com/en), and describe the challenges in obtaining accurate
estimates of the occurrence of VVC and RVVC.
Overview of condition
VVC, more generally referred to as a vaginal yeast infection, is
characterized by vulvar erythema, excoriation, pruritus, and an abnormal
“cheese-like” or watery vaginal discharge. VVC also may be accompanied by
a change in vaginal odor [2, 4, 14e16]. Symp-toms found among patients with
vaginal cultures positive for Candida range from none to many [4]. Candida
albicans most commonly causes VVC, accounting for 85%e90% of all cases,
with the remainder attributed to C. glabrata, C. krusei, C. famata, and C.
tropicalis [2, 13, 17]. VVC is rare before menarche, peaks during

http://dx.doi.org/10.1016/j.annepidem.2017.08.010 1047-
2797/ 2017 Elsevier Inc. All rights reserved.
576 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582
the reproductive years, then declines after menopause [2, 4, 18]. Risk factors
for sporadic VVC include sexual activity, contraceptive use, antibiotic use,
carbohydrate intake, and diabetes [4, 18e20].
Few descriptions of the natural history of VVC exist in the medical or
scientific literature, but clinical impression is that the initial acute infection is
often followed by one or more episodes. This was confirmed by the few
studies that directly estimate recurrence. Yue et al. [21] followed 400 Chinese
women seen at the Sichuan University of China Hospital with culture-
confirmed VVC for up to two years. After effective treatment that cured all
symptoms, 53% (212/400) had a second episode within two years. Amouri et
al. [22] identified 231 culture-confirmed Tunisian VVC patients, and followed
71 of those patients for one year. Sixty percent (49/71) of those followed
experienced a recurrence. Richter et al. [9] obtained yeast isolates from 429
culture-confirmed Iowan VVC patients over a 39-month period. Almost one-
fifth (19.6% [84/429]) had multiple positive cultures during the study period.
RVVC has been defined as 3 or more, and as 4 or more, episodes of VVC
within a 12-month period [18, 23]. Behavioral risk factors asso-ciated with
VVC have not been associated with RVVC, but there is some evidence of an
association between polymorphisms in genes coding for innate immunity and
RVVC. The most complete evidence is for a polymorphism in mannose-
binding lectin (MBL2), which binds fungi as part of host innate immune
response. In a meta-analysis, Nedovic et al. [24] estimated that heterogeneity
in the MBL2B allele increased the risk of RVVC by as much as four-fold and
of VVC by 2.5 times. Studies by Rosentul et al. [25] identified a
nonsynonymous polymorphism in toll-like receptor 2 (Pro631His, rs5743704)
that occurred almost three times more frequently among RVVC patients (n ¼
119) than 263 healthy controls. Finally, in a multicountry study of 270 RVVC
patients and 583 healthy controls, presence of the 12/9 genotype of the
NLRP3 gene (which encodes the component of the inflammasome that
processes inflammatory cytokines IL-1band IL-18) occurred more frequently
in cases than controls [26].
Since 1967, when azoles were approved for treatment of VVC and RVVC
[27], VVC has been treated using antifungal therapies. Resistance to
antifungal therapies remains rare [28, 29] but prolonged treatment and the
widespread availability of over-the-counter azole agents since 1990 increases
the potential for development of resistant strains [30]. In our analysis of
1
NAMCS data from 2006 to 2011, antifungals were prescribed at 27% of
visits where a VVC diagnosis was made [31]. This is likely an un-derestimate
of use, as women may have been directed by their health care provider to
purchase over-the-counter medication; further, many women may self-
diagnose and treat.
RVVC imposes a significant health burden
In addition to physical discomfort, RVVC imposes significant
psychological and monetary costs [10, 11, 32]. Compared with women
presenting for family planning services with no history of RVVC, women with
RVVC had lower self-esteem, felt under greater stress, were more likely to
suffer from clinical depression, and were
1
NAMCS is a national probability-based sample survey of patient visits to nonfederal, office-
based physicians during a 1-week reporting period. In our anal-ysis, data were weighted to the
2006e2011 age-specific female populations ac-cording to the United States census. A diagnosis
code of 1121 (candidiasis of vulva and vagina) was used to define VVC. The diagnosis code of
61,610 (vaginitis un-specified) was also included if there was a prescription for fluconazole
(drug entry code 93,215). VVC was also considered for diagnosis code 1129 (candidiasis un-
specified) where vaginal symptoms were present (reason for visit 17,650, 17,701, 17,600).
Incidence and prevalence rates cannot be calculated from these data because the estimates are in
terms of visits and not persons.
less satisfied with their lives in general. RVVC also interfered with emotional
and sexual relationships [33]. In our analysis of the NAMCS,
psychotherapeutic agents were prescribed twice as frequently during visits
where a VVC diagnosis was made than during visits for family planning (6%
vs. 3%; p-value ¼ 0.1.) [31]. Further, in an internet panel survey of 620
women with RVVC in six countries (USA, France, Germany, Spain, Italy, and
the UK), 53% reported anxiety/depression compared with less than 20% in the
general population [12].
In qualitative interviews of 127 women with RVVC in the United States,
nearly 80% of women reported that yeast infections affected their personal
lives including the ability to socialize and exercise, and half reported fear of
social interaction and dating. Approxi-mately 40% of women surveyed
considered VVC a very significant burden on their lives; the most extreme
burdens were discomfort from symptoms, avoidance of sexual activity, and
out-of-pocket costs due to prescription or over-the-counter drugs and office
visit copays [34].
At a population level, out-of-pocket costs due to treatment and office visits
are significant. During 2006e2011, 5 of 1000 women visits were for VVC
among women aged 15 and over during the one-week NAMCS reporting
period [31].
VVC also reduces productivity: in qualitative interviews of 127 women
1
with RVVC in the United States, /3 of respondents had missed work due to
their yeast infection [34]. Aballéa et al. [12] estimated productivity loss due to
RVVC as an average of w33 work hours per year, or approximately $1261 in
2011 dollars.
VVC and RVVC diagnosis
Symptoms of VVCditching, inflammation, and dis-chargedoverlap with
those of other common vaginal infections, and Candida can be found even
when it is not the cause of symp-toms. For example, Candida can be isolated
from the vaginal cavity of an estimated 20% to 30% of women with bacterial
vaginosis [35]. Moreover, an estimated 12%e30% of nonpregnant [36e38],
and 9%e20% of pregnant women [36, 39e41], carry C. albicans asymp-
tomatically in the vaginal cavity. Uncertainty in diagnosis is somewhat
problematic clinically but poses a significant challenge for estimating VVC
and RVVC incidence. Most estimates of VVC and RVVC rely on self-report
of physician diagnosis [6e8, 34].
To evaluate the extent that physician misdiagnosis might bias incidence
and prevalence estimates based on physician visits or patient self-report
(ignoring issues of recall), we conducted a review of recent medical
textbooks, current CDC guidelines, and scholarly journal articles (presented
visually in Tables 1 and 2). Information from 10 articles, nine medical texts,
and CDC guide-lines were used to construct graphics comparing diagnostic
technique recommendations (see Table 3 for search terms). Green dots
represent diagnostic techniques or symptoms recommended by the reviewed
sources as primary, reliable, and encouraged ways to diagnose a VVC
infection without any caveats as to sensitivity, specificity, predictive value, or
clinician access. Although medical texts have fairly uniform recommendations
(Table 1), they are not always consistent with the scientific liter-ature (Table
2). Further, while KOH microscopy or some other confirmatory objective
laboratory measure is consistently rec-ommended in texts and the scientific
literature, it is rarely used in medical practice, with clinicians instead relying
on signs and symptoms [58, 59].
Unfortunately, the sensitivity and specificity of symptom-based diagnosis
of VVC is low [59e62], so both overdiagnosis and un-derdiagnosis are
possible. In a review of studies from 1966 to 2003, approximately 30% of
symptomatic women experiencing VVC remained undiagnosed after a clinical
evaluation [62]. Even
 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582 577

Table 1
*
Diagnostic recommendations in medical textbooks; 2006e2016 [14e16, 42e48]

* Green dots represent diagnostic techniques or symptoms recommended by the authors as primary, reliable, and encouraged ways to diagnose a VVC infection without any caveats as to sensitivity,
specificity, predictive value, or clinician access. A diagnostic technique was coded as yellow if it was described as being a secondary diagnosis technique, dependent on the failure of the first (i.e., “may
be obtained but seldom necessary”) or if mention was made as to its unreliability due to issues with sensitivity, speci ficity, predictive value, or clinician access, without a provision being made for the
technique still being the best available. An asterisk indicates a diagnostic technique was explicitly named the “gold standard”.

when augmented with a recommended laboratory technique such as KOH
microscopy and culture, problems with sensitivity and specificity remain. As
summarized in Figures A1 and A2, KOH microscopy has a low sensitivity,
and although culture has a much better sensitivity, it has low specificity, due
in part to asymptom-atic carriage of Candida. Therefore, even if there were
accurate reporting of physician diagnosis it is likely that some diagnoses were
in error.
Further, since 1990 antifungals for VVC treatment have been available
over the counter [30]. As a result, women have been able
to purchase treatments for VVC without consulting a physician first. Thus
VVC prevalence estimates based on physician diagnosis likely underestimate
the true prevalence [30, 63e65].
Incidence and prevalence estimates based on sales of anti-fungals are also
problematic. Although women often feel confi-dent in their ability to diagnose
a yeast infection, they often mistake nonspecific symptoms of other vaginal
infections for VVC [66e68]. Only 11% of women completing a questionnaire
designed to test their knowledge of different vaginal conditions accurately
diagnosed common causes of vaginitis after reading
578 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582

Table 2
*
Diagnostic techniques in scientific literature; 2006e2016 [13, 18, 42, 49e57]

* Green dots represent diagnostic techniques or symptoms recommended by the authors as primary, reliable, and encouraged ways to diagnose a VVC infection without any caveats as to sensitivity,
specificity, predictive value, or clinician access. A diagnostic technique was coded as yellow if it was described as being a secondary diagnosis technique, dependent on the failure of the first (i.e., “may
be obtained but seldom necessary”) or if mention was made as to its unreliability due to issues with sensitivity, speci ficity, predictive value, or clinician access, without a provision being made for the
technique still being the best available. An asterisk indicates a diagnostic technique was explicitly named the “gold standard”.

classic case scenarios. Women with a prior VVC diagnosis did somewhat
better, but still poor (34.5%) [67]. In a study of women purchasing over-the-
counter medication for a self-diagnosed VVC infection, only one-third of
women actually had VVC, and an additional 20% who did have VVC
infection also had another type of vaginitis, which may have contributed to
symptoms and required a different treatment. Prior clinician recommendation
to use over-the-counter medication did not increase accuracy of self-diagnosis
[68].
Estimated prevalence of VVC and RVVC: results of a systematic
literature review
To estimate the prevalence of VVC and RVVC, we conducted a systematic
literature review of papers published between 1980 and 2016 using the search
terms shown in Table 3, which also shows the number of articles identified per
term. After limiting to articles from scholarly journals and removing reviews,
we found nine articles estimating VVC estimates (Figures A3 Appendix).
We compare the
 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582 579

Table 3 episode of VVC estimated 5% of women had 4 or more VVC episodes in the
Search terms used in the systematic literature review by section, years 1980e2016 past 12 months [12]. In a survey used to identify RVVC pa-tients for
Section Search term used Number results qualitative interviews, 6.3% of 2391 U.S. women reported four or more VVC
before episodes in the past year [34]. A 2010 Brazilian study of 669 nondiabetic
refinement
women in a cervical cancer screening program reported 8.2% of participants
VVC prevalence VVC prevalence 409 with culture-confirmed acute VVC with 20% of these (1.6% overall) reporting
graphic Vulvovaginal candidiasis prevalence 1348
4 or more episodes in the past year [70]. Although not specifically/precisely
VVC lifetime prevalence 92
Studies of VVC prevalence 392
assessing 1-year period prevalence, these three surveys provide relatively
RVVC RVVC prevalence 122 consistent initial indications of a period prevalence on the order of 5%e8%.
prevalence Recurrent vulvovaginal candidiasis 1614 The inconsistency in estimates of current and lifetime RVVC prevalence
graphic prevalence needs further study. Some of the in-consistencies may be attributable to the
RVVC lifetime prevalence 38
different age structures of the populations. It is also possible, as we show
Dot Graphic Vulvovaginal candidiasis diagnosis 1782
VVC diagnostic techniques 197 below, that some of the inconsistency is attributable to a recall effect. Further,
Problems with VVC diagnosis 255 most studies do not include women in the oldest age groups or have limited
RVVC diagnosis 123 precision to estimate their VVC prevalence (even if recall were perfect).
Vulvovaginal candidiasis guidelines 766
VVC (using Taubman Health Sciences 49
Library)
Yeast infection (using Taubman Health 39,452
Sciences Library The proportion of VVC patients who suffer from or report re-currences
Introduction Vulvovaginal candidiasis 3702 range from 6% to 20%, depending on the study population and methods.
Vulvovaginal candidiasis risk factors 1557 Active surveillance of women at an Iowan VVC clinic between January 1998
Vulvovaginal candidiasis age 1517
Vulvovaginal candidiasis genetics 882
and March 2001 found 19.6% (84/429) experienced multiple culture-
Vulvovaginal candidiasis blood 1259 confirmed VVC episodes [9]. An Ital-ian prospective survey of women at
hospital and gynecology clinics between October 1999 and March 2001 found
10% reported a prior history of RVVC [8]. A 2011 Tunisian study of 231
women with culture-confirmed VVC found 6.1% that had a VVC episode in
results of this review with an analysis of the cumulative probability of the previous year went on to have three episodes in the year following
diagnosis by age 50 estimated using data from an online seven-country enrollment [22]. A 2006 VVC study of 576 Greek women found that 8.5%
omnibus opinion poll conducted by Ipsos Health, France (49/576) had four or more documented positive cultures of symptomatic VVC
(https://www.ipsos.com/en; epidemiologic survey 11-030783-01; results of in the prior year to enrollment [71].
six of these countries were reported in Foxman et al. 2013 and Aballea et al.
2013). Incidence and prevalence cannot be esti-mated using NAMCS data We used data from the 2011 Ipsos survey of 7345 participants in seven
because of how the data are collected. countries to estimate the probability of VVC and of RVVC given VVC by age
50 using the method of Kaplan-Meier [72]. We report the cumulative
Estimated prevalence of VVC and RVVC probability by age 50 because at older ages the sample sizes were relatively
small and estimates less stable. Further, it was roughly 50 years ago that the
The annual incidence of VVC is high. In a random digit dialing survey of regular treatment of VVC with antifungals became commonplace [27].
1698 white Americans aged 18 and older, 26.4% reported a physician-
diagnosed yeast infection during the past 5 years or 5.2% per year. Among the VVC occurrence was defined by self-report of physician diag-nosis; and
144 black Americans participating in the sur-vey, 46.5% reported a physician- RVVC occurrence was by self-report of any 12-month period with 4 or more
diagnosed yeast infection during the past 5 years or 9.3% per year [69]. Self- yeast infections. Since age at time of first VVC was not recorded, age at
reported 5-year incidence decreased with age, from 38% among 18e29 year response to survey was used as a proxy variable in the analysis. To estimate
olds to 8% among those 65 and older. the cumulative proba-bility of RVVC in the total population, we multiplied
cumulative probabilities of VVC occurrence by the cumulative probability of
Lifetime VVC prevalence has been estimated via self-administered RVVC occurrence given VVC occurrence. To assess the effects of recall, we
questionnaires, random digit dialing surveys, and internet panels in different analyzed the proportions of RVVC patients in the study by age category and
populations: U.S. college students [20], a random sample of telephone by self-reported age at first RVVC. There were w1000 participants per
numbers in the United States [69], and two different selections of participants country, and sampling was stratified by age for each country.
in internet surveys in six countries [7, 64]. Regardless of method and study
population, the percent of women reporting VVC infection over their
lifetimes is high, ranging from 29% to 49% [4, 7, 20, 64]. Although these The cumulative probability of self-reported physician-diagnosed VVC by
surveys are subject to errors, as noted previously, there can be little doubt that age 50 averaged over the seven countries was 39%, similar to previous
VVC is a common condition. estimates of lifetime VVC prevalence (Table 4). Given a VVC episode, the
average overall probability of experiencing RVVC by age 50 was 23%; which
There is similar heterogeneity in methods used to estimate RVVC translates to a lifetime RVVC prevalence by age 50 of 9%. This estimate is
prevalence [6, 7, 34, 35]. Eight percent of 2000 U.S. women aged 18 years of also remarkably close to other estimates for RVVC, which range from 6% to
age or older participating in a random digit dialing survey reported 10% [6, 7]. Estimates were very similar across the seven countries with the
experiencing four or more infections over a 1-year period sometime in their exception of France and Japan, which were lower. This difference may stem
lives [6]. A 2013 web-based survey of women from six countries estimated from cultural differences in response to disease, access to care, risk behavior,
lifetime prevalence (defined as a 1-year period with 4 or more VVC episodes) or the study questions [7].
at 9% [7]. Estimates of RVVC prevalence in the past year (period prevalence)
are higher than one might expect given estimates of lifetime prevalence. A If memories were perfect, and the occurrence of RVVC has not changed
cross sectional internet panel survey of U.S. and European women aged 18 to with time, we would expect that those at the oldest age groups would have the
65 with at least one health care professionalediagnosed most RVVC. This is not the case; the group reporting the most RVVC was
aged 19 to 25 (Table 5). Further
580 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582

Table 4 Table 5
Estimated cumulative probability by age 50 of vulvovaginal candidiasis (P(VVC)), cumulative Estimated prevalence of recurrent vulvovaginal candidiasis (RVVC) given a prior VVC, by self-
probability by age 50 of recurrent vulvovaginal candidiasis given prior VVC (P(RVVCjVVC)), reported age at first RVVC. Data from 2011 Ipsos survey (n ¼ 7345) (Ipsos Health, France
*
and estimated cumulative probability by age 50 of RVVC in the total population Data from [https://www.ipsos.com/en]depidemiology survey 11-030783-01 [June 2011]don behalf of
2011 Ipsos survey (n ¼ 7345) (Ipsos Health, France [https://www.ipsos.com/en]dEpidemiology Pevion Biotech, Switzerland
survey 11-030783-01 [June 2011]don behalf of Pevion Biotech, Switzerland)
Age at First Current age
RVVC
12e18 19e25 26e35 36e45 46e55 56e65
Country P(VVC) P(RVVCjVVC) *
P(VVC) P(RVVCjVVC)
12e18 5 (100%) 20 (25%) 13 (8%) 10 (7%) 3 (3%) 1 (1%)
France 0.32 0.14 0.04
19e25 0 61 (75%) 66 (40%) 40 (27%) 28 (28%) 11 (15%)
Japan 0.23 0.17 0.04
26e35 0 0 84 (52%) 55 (38%) 22 (22%) 24 (32%)
US 0.40 0.24 0.10
36e45 0 0 0 41 (28%) 22 (22%) 6 (8%)
Italy 0.48 0.25 0.12
46e55 0 0 0 0 25 (25%) 16 (22%)
UK 0.36 0.25 0.09
56e65 0 0 0 0 0 16 (22%)
Germany 0.43 0.27 0.12
Ever VVC of 19% 29% 25% 20% 18% 17%
Spain 0.49 0.28 0.13
ever RVV
Averages 0.39 0.23 0.09

* Results from KaplaneMeier analysis predicting survival to age at first self-reported VVC,
and age when at time of first 12-month period with 4 or more VVC episodes among those with
VVC.
analysis suggests that older women might have forgotten previous RVVC
episodes, as based on the overall estimates, we would expect RVVC to occur
equally likely in each age group, but older women tend to not report having
experiencing RVVC in the youngest age categories (Table 5).
We found only one study that prospectively followed women to estimate
the risk of RVVC. In this 2015 study of 400 women of reproductive age with
culture-confirmed symptomatic VVC recruited through West China Second
University Hospital [21], 212 of 400 women experienced one recurrence
(53%, 95% CI: 48%e58%) within the 2 years of follow-up. Thirty percent
(95% CI: 26%e35%) had two recurrences, 17.5% (95% CI: 14%e21%) three
recurrences, and 9% (95% CI: 6%e12%) four recurrences.
28% of them will go on to experience RVVC, an estimated 4% to 13% of
women will have a 1-year period where they experience 4 or more VVC
episodes by age 50 (Fig. 1).
There is some evidence that VVC risk varies by geographic area. VVC
prevalence varied by country in the seven-country Ipsos internet survey (from
23% to 49%). Further, in our analysis of NAMCS data, 17.4% of visits for
VVC were in the Northeast, 21.7% in the Midwest, 38.8% in the South, and
22.1% in the West [31]. In the 2011 Ipsos Health survey of U.S. women, the
percent of women who responded that a health care provider had told them
that they had a vaginal yeast infection, vaginal thrush, or VVC was also
slightly higher in the Southern United States. How much of this variation is
attributable to differences in diagnosis, variation in modifiable risk factors, or
population variation in genetic susceptibility is unknown.

The estimated risk of RVVC following VVC in the Chinese study is very
similar to estimates from the literature based on the propor-tion of women
with a history of VVC that self-report a 12-month period with three or more
VVC episodes [7, 69]. It is also similar to the cumulative probabilities of
RVVC by age 50 given VVC in the 2011 Ipsos survey (Table 4). Assuming
that 23 to 49% of all women will experience at least one episode of VVC by
age 50, and 14% to
Looking toward the future
Estimating the prevalence and incidence of common conditions where
there are not uniformly adapted criteria for diagnosis and self-treatment is
challenging. While it is clear that VVC and RVVC impose a substantial
burden, precisely quantifying that burden using existing databases is fraught
with error. For example, a major

Fig. 1. Estimated cumulative probabilities of vulvovaginal candidiasis (VVC), recurrent vulvovaginal candidiasis (RVVC) given VVC, and RVVC by age 50 in seven countries. Estimates from a
KaplaneMeier analysis. Data from 2011 Ipsos survey (n ¼ 7345) (Ipsos Health, France [ https://www.ipsos.com/en]depidemiology survey 11-030783-01 [June 2011]d on behalf of Pevion
Biotech, Switzerland).
 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582
problem with using NAMCS data is that the denominator is visits, not women
so prevalence and incidence cannot be estimated. Further, in NAMCS not all
visits coded as VVC include a prescription for an antifungal. This is probably
because antifungals are available over the counter, but we cannot be certain
that indeed VVC was diagnosed. Other databases pose different challenges,
but all are subject to vagaries in diagnosis; in practice VVC is rarely
confirmed microbiologically. Ideally, VVC and RVVC incidence would be
esti-mated by following a large cohort of women representative of the general
population using uniform criteria for diagnosis that in-cludes laboratory
confirmation. Appropriately powered cohort studies following women with
first VVC through multiple re-currences using uniform diagnostic criteria that
includes microbi-ologic confirmation and assessment of risk factors would
greatly enhance our understanding of the natural history of RVVC.
In summary, the burden of VVC and RVVC on the population is high, and
the prevalence varies by age and geographic area sug-gesting there may be
modifiable risk factors. The burden probably varies with age, but further
primary studies are required to quantify that burden across age groups.
Although the individual impact of VVC can be low or negligible, for women
experiencing RVVC, the physical, psychological, and monetary costs can be
substantial. In-terventions to reduce risk of VVC and of RVVC following
VVC would be most welcome.
Acknowledgments
This work was funded by NovaDigm Therapeutics, Brookline,
Massachusetts. The authors thank Anna Cronenwett for secretarial support.
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Appendix

Figure A1. Estimated sensitivity estimates (relative to culture) of vulvovaginal candidiasis diagnostic techniques from the scientific literature (see methods).

Figure A2. Estimated specificity (relative to culture) estimates of vulvovaginal candidiasis diagnostic techniques from the scientific literature (see methods).
582.e2 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582

Figure A3. Prevalence estimates of self-reported physician-diagnosed vulvovaginal candidiasis per 100 population: results of a systematic literature review (1980e2016; see methods).
 F. Blostein et al. / Annals of Epidemiology 27 (2017) 575e582
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582.e3
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