Risk factors for recurrent vulvovaginal candidiasis in women receiving
maintenance antifungal therapy: Results of a prospective cohort study
Divya A. Patel PhD,
Brenda Gillespie PhD
Jack D. Sobel MD,
Debbie Leaman BSN,
Paul Nyirjesy MD,
M. Velma Weitz MSN,
Betsy Foxman PhD*,
Department of Epidemiology,
University of Michigan School of Public Health, Ann Arbor, Micha;
Center for Statistical Consultation and Research, University of Michigan, Ann
Arbor, Michb; Division of Infectious Diseases, Wayne State University
School of Medicine, Detroit, Michc; and Department of Obstetrics and
Gynecology, Thomas Jefferson Medical College, Philadelphia, Pa dUSA
Received 1 August 2003; revised 28
October 2003; accepted 17 November 2003
Abstract
The purpose of this study was to examine risk factors for symptomatic
vulvovaginal candidiasis episodes among women with recurrent vulvovaginal
candidiasis (defined as ³4 vulvovaginal candidiasis
episodes in 1 year) who were receiving maintenance antifungal therapy.
A prospective study of 65 women aged ³18 years with
recurrent vulvovaginal candidiasis who attended vaginitis clinics in Detroit,
Mich, and Philadelphia, Pa.
The 9-month risk of vulvovaginal candidiasis recurrence was 41.8%. Almost two
fifths of the women reported activity limitations because of vulvovaginal
candidiasis episodes, most or all of the time. Younger women and those women
with a history of bacterial vaginosis were at increased risk of vulvovaginal
candidiasis episodes. Behavioral factors that were associated significantly with
increasing vulvovaginal candidiasis recurrence ³2- fold
included wearing pantyliners or pantyhose and consuming cranberry juice or
acidophilus-containing products.
The use of pantyliners or pantyhose, consumption of cranberry juice or
acidophil-containing products, a history of bacterial vaginosis, and age <40
years were positively associated with a symptomatic vulvovaginal candidiasis
episode.
Keywords: Candidiasis; Vulvovaginal; Recurrent
vulvovaginal candidiasis and Risk factors.
Article Outline
Three-fourths of all women experience at least 1 episode of vulvovaginal
candidiasis (VVC) in their lifetime; about one half of these women will
experience a recurrence.[ 1 ] Approximately 5% of women with VVC develop recurrent VVC
(RVVC),[ 2 ] which is defined usually as ³4
episodes of VVC that occur within a 12-month period. Associated symptoms and
signs include pruritis, burning, soreness, abnormal vaginal discharge,
dyspareunia, and vaginal and vulvar erythema and edema,[ 3 ] which may cause strain in sexual and marital
relations.[ 4 ]
Known predisposing host factors, which include uncontrolled diabetes
mellitus, immunosuppression, pregnancy, and hormone replacement,[ 5 ] only partially explain RVVC.[ 6 ] Broad-spectrum antibiotic use has been suggested as a risk
factor for both acute[ 7 ] and recurrent[ 4,
8 ] VVC. Most popular literature focuses on behavioral factors,
but there are relatively few studies of these factors,[ 9 ] particularly for recurrent infections. Dietary
factors,[ 10 ] clothing habits,[ 11 ] personal hygiene,[ 11,
12,
13 ] contraceptive use,[ 8,
11,
12,
13 ]and sexual practices[ 8,
11,
12,
14,
15 ] have been studied as risk factors for recurrence. However,
the results have not been conclusive.
We describe the 9-month risk of a symptomatic VVC episode among a cohort of
women with RVVC who received antifungal maintenance therapy. In addition, we
identify potential risk factors and describe the disease impact.
We conducted a prospective cohort study among 65 women with RVVC.
Participants were recruited between 1998 and 2001 from clinics that specialized
in the evaluation of women who had been referred for chronic vulvovaginal
symptoms at Wayne State University (Detroit, Mich) and Temple University
(Philadelphia, Pa). The study protocol and consent form were approved at each of
the study sites by the local institutional review board, and all women provided
written informed consent.
Female outpatients aged ³18 years who had an acute,
symptomatic, culture-confirmed episode of VVC and a history of ³4 episodes of VVC in the previous 12 months (including the
current episode) were enrolled. Among patients who had received antifungal
maintenance therapy within the previous 12 months, a history of at least 4
episodes of vaginal candidiasis within the year before the start of maintenance
therapy was necessary for inclusion. At least 1 of the previous VVC episodes
must have been diagnosed by a health care provider. Some participants were
either previously or currently enrolled in an ongoing clinical trial of
fluconazole antifungal maintenance therapy; antifungal drug status was validated
on enrollment with clinical information. Patients with negative Candida
cultures were excluded. Women who did not provide both enrollment and follow-up
data for at least 1 month were also excluded.
At enrollment, we collected a detailed medical history and conducted a
thorough pelvic examination, measurement of pH, amine testing, and microscopic
examination of vaginal secretions with the use of 10% potassium hydroxide and
normal saline solution. A swab sample from the middle one third of the vagina
was placed on Sabouraud dextrose agar plates. Final confirmation of the
diagnosis depended on positive Candida cultures, which were evaluated for
the formation of germ tubes and chlamydospores. All yeast isolates were
identified to the species level with the Analytical Profile Index (API) method
(BioMérieux, Inc, Durham, NC). Laboratory tests and the vaginal examination that
had been performed at enrollment were repeated for women who returned to the
vaginitis clinics for signs and symptoms that were consistent with VVC infection
during the follow-up period.
Patients completed 1 self-administered questionnaire at enrollment and
another monthly self-administered questionnaire for up to 9 months after
enrollment. If the questionnaire was not returned within 2 weeks, the research
nurse called the patient and conducted an interview. A small incentive ($2.00)
was included with each questionnaire.
A recurrent episode of VVC during the follow-up period was defined as (1)
self-report (in the follow-up questionnaire) of health care provider–diagnosed
VVC or (2) a documented visit to the vaginitis clinic for signs and symptoms of
VVC during the follow-up period, with laboratory results that were consistent
with VVC infection. The species of yeast that was present at recurrent episodes
of infection were determined from laboratory results, when available. Because of
the small number of positive yeast cultures (n = 14 cultures) that were given in
the laboratory data and the difficulty in the interpretation of a positive yeast
culture that was given as diagnostic of infection (many women harbor yeast as
part of their vaginal flora), we relied on health care–provider diagnoses of VVC
as reported in the follow-up questionnaires to be the outcome variable for most
analyses.
The Kaplan-Meier estimator of VVC recurrence risk, which adjusts for varying
follow-up times, was calculated. Crude associations between VVC recurrence and
fixed covariates (such as marital status and race) were described with
cumulative incidence (risk) ratios and 95% CIs. Crude associations between RVVC
and time-varying covariates (such as sexual practices and health behaviors) were
described with rate ratios and 95% CIs.
To explore further the associations of biologically plausible host factors
that were identified in the bivariate analyses with risk of RVVC, we fit a
series of time-dependent logistic regression models that predicted RVVC that
adjusted for within-subject correlation among observations. Because of the small
sample size, we fit a series, rather than a single model; each model included
antifungal maintenance pills that were taken in the previous week and cranberry
juice consumption in the previous week, which were the 2 strongest, biologically
plausible factors that occurred with sufficient frequency to facilitate model
convergence, in addition to a time-varying characteristic of interest. To
account for the time lag between the hypothesized risk factor (such as use of
antibiotics) and clinical manifestations of VVC, associations between VVC and
factors were calculated in the same week as and the week before VVC diagnosis.
We used generalized estimating equations that were specified with an independent
working correlation structure to account for within-subject correlation among
observations. To evaluate the representativeness of our study population,
selected demographic characteristics of participants were compared with those of
40 women who participated in a random-digit-dialing (RDD) telephone survey,
which has been described elsewhere,[ 16 ] who reported at least 4 episodes of VVC in the 12 months
before the survey. All data management and analyses were preformed with SAS
software (version 8.2; SAS Institute Inc, Cary, NC).
Of the 42 women who were identified at Wayne State University, 1 woman had a
negative Candida culture at baseline; 1 woman did not complete the
enrollment questionnaire, and 1 woman withdrew from the study, which left a
final sample of 39 women (95% participation of those eligible). Of the 33 women
who were identified at Temple University, 1 woman had a negative Candida
culture at baseline; 3 women were excluded because they did not provide at least
1 month of follow-up data, and 3 women withdrew from the study, which left a
final sample of 26 women (82% participation of those eligible). Thus, the total
study population consisted of 65 women. Sixty-one participants (94%) completed
at least 3 of the follow-up questionnaires. On average, participants provided
questionnaire data for 7.8 months of the total 9-month study period.
Most participants were white (89%), married (66%), had attended at least some
college (65%), and were employed full time (62%). Participant ages ranged from
19 to 61 years, with a mean of 35.3 years. Participants reported an average of
6.3 infections in the year before enrollment. Participants from Wayne State and
Temple Universities were similar with respect to the average number of
infections in the previous year (5.9 vs 6.9 infections; P = .5, by
t-test), age, race, marital status, employment status, highest level of
education attained, parity, lifetime number of sex partners, lifetime number of
yeast infections, and other factors
The number of lifetime sex partners ranged from 1 to 50, with an average of
7.1 partners (median, 5 partners; SD, 8.9 partners). In the year before
enrollment, participants reported an average of 1.3±1.2 sex partners, with most
participants (87%) reporting only 1 sex partner during that year. No
participants were pregnant at enrollment, but 4 participants reported pregnancy
during the follow-up period. No participants had human immunodeficiency virus; 3
participants had diabetes mellitus.
At enrollment, the most common vaginal symptoms were itching (92.2%),
soreness (90.8%), redness (90.8%), and discharge (85.9%). Other vaginal symptoms
included pain (80.4%), burning (70.3%), dryness (66.1%), and odor (50%). Most
participants (81%) reported activity limitations at least some of the time
because of their current yeast infection; 15 participants (29.4%) reported
activity limitations most of the time, and 5 participants (9.8%) reported
activity limitations all of the time.
Of the 55 women (84.6%) with positive vaginal cultures at enrollment, 50
women (90.9%) had Candida albicans; 4 women (7.3%) had mixed infection (
C albicans plus either C parapsilosis, C guillermondii,
C glabrata, or Saccharomyces cerevisiae), and 1 woman (1.8%) had
C glabrata alone. All 5 women with negative baseline vaginal yeast
cultures had evidence of past positive vaginal yeast cultures and were receiving
antifungal suppressive prophylaxis.
At enrollment, 13 participants (20%) reported having treated their current
infection with medication before contacting a doctor or nurse; 4 women (31%) had
used over-the-counter medications; 4 women (31%) had used prescription
medications that were remaining from a previous treatment, and 5 women (38%) did
not specify the type of treatment. Nearly one half of the women (31/65 women)
reported ever receiving maintenance therapy (regularly taking a drug to control
yeast infections even in the absence of symptoms). Eleven women (17%) reported
that they currently were receiving some type of maintenance regimen to control
their yeast infections at the time of enrollment; however, a review of clinical
information revealed that only 2 of these women were receiving a fluconazole
regimen that had been prescribed by a health care provider.
Almost all participants (64/65 women) were prescribed fluconazole maintenance
regimens (typically in a dosage of 150 mg fluconazole every 4 days for 3 doses,
followed by 100 mg once a week) at their enrollment visit. The remaining
participant was allergic to fluconazole and was prescribed a maintenance regimen
of boric acid vaginal suppositories at enrollment (600 mg twice a day for 14
days, followed by 1 suppository nightly for 6 weeks). However, comparison of
self-reported consumption of antifungal pills to prevent a yeast infection with
prescribed regimens showed that some women did not follow the regimens as
prescribed. To account for this discrepancy, we used a combination of
prescription information from the clinical examinations and self-reported
antifungal pill consumption from the follow-up questionnaires to classify women
as being on maintenance therapy on a week-by-week basis.
Twenty-five of the 65 women had at least 1 episode of self-reported, health
care provider–diagnosed infection during the 9-month follow-up period; 19 of
these women (76%) had 1 episode; 3 women (12%) had 2 episodes; 1 woman (4%) had
3 episodes, and 2 women (8%) had 4 episodes, for an overall adjusted 9-month
risk of at least 1 recurrence of 41.8%. Self-report of health care
provider–diagnosed VVC was most common at months 1 and 4 (Figure
1); however, differences by month were not statistically significant (
P = .82, by c2 test ). The average
monthly incidence of VVC was 7.2% (95% CI, 4.9, 9.5) over the 9-month study
period. Two mutually exclusive categories were created to compare VVC incidence
among women who self-reported taking an antifungal pill for at least 1 week of
the month and those who reported no antifungal usage in the month (Figure
1). There were no episodes of VVC in months 1, 2, 8, and 9 among women who
reported no antifungal usage, and no episodes of VVC in month 7 among women who
reported any antifungal usage.
Collectively, study participants reported 102 consultations with a health
care provider regarding vaginal symptoms during the study period (17% by
telephone consultation; 56% in-person, and 28% by both telephone consultation
and in-person). Of the 36 VVC episodes that were diagnosed by a health care
provider, 8 episodes (22%) involved telephone consultation; 19 episodes (53%)
involved in-person consultation, and 9 episodes (25%) involved both telephone
and in-person consultations.
Nine of the 36 VVC episodes (25%) were documented clinically. The average
time to first clinically documented RVVC was 4.11±3.3 months after enrollment.
Most of these clinically documented episodes (8/9 episodes) involved the same
species as the enrollment episode ( C albicans, 7 cases; C
glabrata, 1 case). The remaining woman had both C albicans and S
cerevisiae at enrollment, then only C albicans at recurrence.
The unadjusted risk of VVC decreased with increasing age group ( P =
.03, by c2 test; - Table: [ 2]). Participants who had a health care provider diagnosis of
bacterial vaginosis (BV) in the past were more than twice as likely to report an
episode of VVC during the study period. Participants from Wayne State University
and those who were white were significantly less likely to report an episode of
VVC during the study period.
Women who took antifungal pills in the week before VVC were one-half as
likely as women who did not to report an episode of VVC during the study period
( - Table: [ 3]). Use of antifungal vaginal creams, boric acid vaginal
suppositories, and estrogen patches all were statistically significantly
associated with increased rates of VVC but were reported by only a few women. No
significant associations between the use of antibiotics (pills or ointment),
antihistamines or other allergy medications, iron or vitamin C supplements, or
estrogen pills and VVC were observed. There were no significant associations
between sexual practices (vaginal, active oral, or receptive oral intercourse)
or contraceptive methods (oral contraceptive, intrauterine device, lubricated or
spermicidal condom) and the rate of VVC. The use of sexual lubricants and VVC,
both in the same week and in the week before VVC, were associated with a 2-fold
increase in the risk of VVC, although the associations were not significant
(data not shown). Women who used pantyliners or pantyhose were more than twice
as likely to report an episode of VVC during the study period; these effects
were significant in the same week and in the week before VVC. No significant
associations between the use of tampons, nylon underwear, or cotton underwear
and VVC were observed. Cranberry juice consumption was associated significantly
with higher rates of VVC in both weeks. Consumption of products that contained
Lactobacillus acidophilus was associated significantly with a higher rate
of VVC in the same week as VVC; a similar, but borderline significant
association was observed in the week before VVC. No significant associations
between candy binges and VVC were observed. There were no significant
associations between illnesses (cold/flu, allergies, eczema, urinary tract
infection, or other illness) and VVC.
After an adjustment was made for covariates in the base model and
within-subject correlation of observations, the use of sexual lubricants,
pantyliners, or pantyhose and eating yogurt or other products that contain L
acidophilus were associated positively with VVC, which increases the risk
approximately 2-fold ( - Table: [ 4]). Women who took antibiotic pills in the same week were at
increased risk of VVC, but the association did not reach statistical
significance. No significant effects of vaginal, active oral, or receptive oral
intercourse on VVC were observed, although engaging in these behaviors appeared
to be protective in the same week as VVC.
Participants did not differ significantly from 40 women with RVVC who were
identified in a RDD survey of the United States in terms of mean number of yeast
infections in the previous year, number of lifetime sex partners, number of sex
partners in the previous year, and distributions of age, race, marital status,
employment, education, age distribution, race distribution, and marital status.
However, participants had fewer children than women in the RDD survey (mean, 1.3
vs 2.6, respectively).
Over a 9-month follow-up period, 41.8% of women with RVVC experienced at
least 1 recurrence. Use of pantyliners or pantyhose, consumption of cranberry
juice or yogurt, a history of BV, and age <40 years were associated
positively with a symptomatic VVC episode. The sample size did not permit
stratification by race or ethnicity; there is a need for additional studies with
larger sample sizes of diverse racial and ethnic distributions to explore
previously suggested associations with black race.[ 17,
18,
19 ]
Local hypersensitivity or allergic reactions triggered by feminine hygiene
practices (including vaginal douching and the use of pantyliners) may predispose
some women to colonization with Candida organisms or symptomatic
infections.[ 20 ] We did not ascertain information about the specific type of
sexual lubricant that was used by participants. Pantyhose and other
tight-fitting garments may predispose some women to infection by increasing the
local perineal moisture and temperature.[ 4 ]
The association between the consumption of yogurt and an increased risk of
VVC was unexpected because Lactobacillus species that are present in
yogurt may interfere with candidal adherence to vaginal epithelial cells and
prevent overgrowth of Candida and certain bacteria.[ 4 ] In a small, unblinded study, Hilton et al[ 10 ] reported fewer episodes of VVC in women who were placed on
oral yogurt therapy. However, a prospective study of women at high risk of
vaginal infections failed to demonstrate that the presence of lactobacilli and
particularly hydrogen peroxide–producing lactobacilli was associated with
subsequent episodes of Candida vaginitis.[ 21 ] Another study found that most lactobacilli-containing
products do not contain the Lactobacillus species as labeled, or contain
other bacteria of undetermined benefit.[ 22 ] Some yogurts have high sugar content, which may elevate blood
sugar levels and increase the risk of symptomatic VVC, particularly among women
who are prone to RVVC.[ 23 ] Controlled studies of yogurt ingestion are needed before it
can be recommended as prophylaxis or therapy. Regarding cranberry juice,
although its acidifying properties should help prevent symptomatic VVC episodes,
the high sugar content in cranberry juice actually may increase risk. The effect
of cranberry juice on the pharmacokinetics of systemic antifungal drugs is not
known.
Sexual intercourse alone has not been shown to alter vaginal Candida
colonization,[ 24 ] but certain sexual practices may be of importance for both
primary transmission of Candida and recurrences of symptomatic episodes.
The few studies that have focused on specific aspects of sexual behavior among
women with RVVC have found positive associations with early sexual
debut,[ 14 ] casual sex partners in the last month,[ 14 ] new sex partner in the last 6 months,[ 12 ] sex during menses,[ 14 ] oral intercourse,[ 14,
15 ] ever engaging in anal intercourse,[ 14 ] and frequency of vaginal intercourse.[ 12 ] We did not find associations between engaging in vaginal or
oral intercourse and risk of RVVC. Frequency of intercourse was not asked in the
questionnaire, and we were unable to evaluate the association between new
partner acquisition and RVVC because most of the women in this study had a
single sex partner in the year before enrollment and during the follow-up
period.
Symptomatic episodes of VVC are observed frequently during courses of oral
systemic antibiotics, particularly broad-spectrum antibiotics,[ 4 ] but we did not observe an association between VVC episodes and
antibiotic use in this group. However, the associated disruption of vaginal
flora may set the stage for RVVC. This is also a possible explanation for the
association with BV history. Misclassification with respect to a participant's
disease history status may also explain the increased risk of symptomatic VVC
among women with a history of BV. The clinical diagnostic criteria for VVC are
nonspecific, and BV is considered in the differential diagnosis of VVC; a past
episode of BV may reflect a misdiagnosed episode of VVC.
The observed association of symptomatic episodes with younger ages is
consistent with previous epidemiologic studies. Women who are aged <45 years
are at increased risk of VVC, and a history of VVC is a strong determinant of a
subsequent episode.[ 17 ]
We had frequent, regular contact with participants to assess health behaviors
and sexual practices, and cases were followed prospectively for an average of
7.8 months of the total 9-month study period, which allowed us to examine the
temporal sequence of exposures and outcomes. Participants were recruited from 2
sites, but the cases were similar to women from a RDD survey who reported ³4 episodes of VVC in the previous year. Still, the results
of this study should be extrapolated with caution. This study does not examine
the natural history of Candida vaginitis; rather, because most of the
women were receiving antifungal maintenance therapy over the course of the
study, it is an examination of recurrences among the women who were treated. We
used participant self-report of a health care provider diagnosis of VVC (either
in-person or with telephone interviews) as the outcome because we did not have
sufficient data to use clinically documented episodes. Future studies that
collect specimens and more detailed clinical data from women with RVVC may
enhance our ability to distinguish between recurrence and reinfection; studies
that perform molecular subtyping are best suited for this purpose.
Although this was not a placebo-controlled study, 40 women (61%) in this
population of women with a history of at least 4 episodes of VVC in the previous
year did not experience a recurrence during the 9 months of follow-up, which
provided some evidence for the efficacy of long-term antifungal maintenance
therapy in the reduction of symptomatic VVC episodes. This study confirms some
of the longstanding challenges that are faced by clinicians and researchers in
the identification of precipitating factors for recurrences among women with
RVVC; few previously identified behavioral risk factors for VVC influenced the
risk of symptomatic episodes. Although it is possible that agent factors and
host defense mechanisms play a greater role than behavioral factors in the cause
of RVVC, the burden of morbidity may be lessened at least for the subgroup of
women in whom precipitating behavioral factors can be identified. A clearer
understanding of host factors that precipitate symptomatic episodes should
provide further insights into the epidemiologic condition and immunopathogenesis
of RVVC and will be important for providing the basis for individually targeted
prevention and control.
We thank Laura Howard for her assistance with data management, Brady West for
his assistance with data analyses, the women who participated in this study, and
Drs James Koopman and Kathleen Ford who provided valuable comments on earlier
versions of this manuscript.
Footnotes
Supported by an unrestricted medical education grant from the Pfizer Corporation
(B.F.) and a grant from the Blue Cross and Blue Shield of Michigan Foundation
(D.A.P.). Presented, in part, as a poster at the 40th Annual Meeting of the
Infectious Disease Society of America Conference, Chicago, Illinois, October
24-27, 2002.
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