Curr Infect Dis Rep (2015) 17:30

DOI 10.1007/s11908-015-0462-0

GENITOURINARY INFECTIONS (J SOBEL, SECTION EDITOR)

Vulvovaginal Candidiasis in Pregnancy

T. J. Aguin & J. D. Sobel

# Springer Science+Business Media New York 2015

Abstract Prevalence studies indicate that Candida species

colonize the vagina in at least 20 % of all women, rising to
30 % in pregnancy. Although, some studies concluded that
pregnant women were more likely to have symptomatic vaginal infections caused by Candida, yet other studies found a
high prevalence of asymptomatic infection only during pregnancy. Most episodes of symptomatic vulvovaginal candidiasis (VVC) occur during the second and third trimesters. The
increased risk of VVC in pregnancy is likely sustained by
pregnancy-related factors, such as immunologic alterations,
increased estrogen levels, and increased vaginal glycogen production. Although evidence is incomplete, there is some
emerging data which suggests that candidiasis in pregnancy
may be associated with increased risk of pregnancy complications, such as premature rupture of membranes, preterm labor,
chorioamnionitis, and congenital cutaneous candidiasis. In
contrast to nonpregnant women, there are no formal studies,
evaluating the use of long-term suppressive maintenance oral
azoles in the treatment of recurrent VVC (RVVC) in pregnancy. Most clinicians do not offer suppressive therapy in pregnancy and prefer to treat individual symptomatic episodes
only utilizing a topical imidazole vaginally for 7 days to minimize systemic exposure to medications.

This article is part of the Topical Collection on Genitourinary Infections

T. J. Aguin
Department of Obstetrics and Gynecology, Wayne State University
School of Medicine, Detroit, MI, USA
J. D. Sobel
Department of Internal Medicine, Division Infectious Diseases,
Wayne State University School of Medicine, Detroit, MI, USA
J. D. Sobel (*)
Harper Hospital, 3990 John R, Room 5934, Detroit, MI 48201, USA
e-mail: Jsobel@med.wayne.edu

Keywords Vulvovaginal . Candidiasis . Recurrent .

Pregnancy

Introduction
Vulvovaginal candidiasis (VVC) is a frequent disease affecting more than 75 % of all women at least once in their lifetime
[1]. In addition, approximately 50 % of these women will also
suffer a single recurrence [2]. A minority of women, 58 %,
experience recurrent vulvovaginal candidiasis (RVVC), which
is defined as 3 episodes per year [2]. Several risk factors,
such as pregnancy, immunosuppression, antibiotic use, and
diabetes, are known to increase the susceptibility to VVC.
As VVC is very common in women during their childbearing
years, it is important to understand the pathology of this disease in pregnancy and its treatment.
Candida species colonizes the vagina in at least 20 % of all
women. This rises to 30 % in pregnancy [3]. Vulvovaginal
candidiasis is the result of Candida albicans in 8595 % of
cases [2, 4] In less than 10 % of cases, non-albicans Candida
species, especially Candida glabrata, or Candida
parapsilosis, Candida tropicalis, Candida krusei, and, in rare
cases, Saccharomyces cerevisiae, cause vulvovaginitis, often
with fewer clinical signs and symptoms [2, 3].

Vulvovaginal Candidiasis in Pregnancy

Several studies found that pregnant women were more likely
than nonpregnant women to experience a symptomatic infection caused by Candida species [3, 5], yet other studies found
a higher prevalence of asymptomatic Candida infection only
during pregnancy [6, 7, 8]. Symptomatic expression of VVC

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Curr Infect Dis Rep (2015) 17:30

during pregnancy depends on clinical, behavioral, and demographic factors [9]. In 2013, an Italian study by Leli et al.
evaluated 344 patients to determine the association of pregnancy and Candida vaginal colonization in women with or
without symptoms of vulvovaginitis. Although pregnant
women were more frequently colonized by Candida, they
found that pregnant women appeared to be less symptomatic
for vulvovaginitis. They divided patients into asymptomatic
and symptomatic, defined by the presence or absence of vaginal pruritis, vaginal discharge, or burning, and the presence of
Candida vaginal colonization. Similar to other studies, they
found that Candida species were recovered in 25 % of patients
symptomatic for vulvovaginitis and in 22.9 % of asymptomatic patients [8].
Fardiazar et al. performed a prospective, comparative, and
analytic study comparing the recurrence rate of VVC during
the first, second, and third trimesters of pregnancy. The mean
recurrence rate was 0.10.48 during the first trimester, 0.92
during the second trimester, and 2.160.63 during the third
trimester. In this study, 90.7 % of patients were in the second
and third trimesters. They found a statistically significant difference between the mean number of symptomatic recurrences during the three trimesters of pregnancy, with most
occurring during the second and third trimesters [4].

number of CD3 and T lymphocytes decrease during pregnancy, as do Th1 and Th2 responses to antigenic lymphocytic
stimulation [1922].
It was initially thought that pregnancy confers general immunosuppression to ensure tolerance of the fetus [23]. However, data indicates that fetus-specific cytotoxic T cell responses can be generated during pregnancy without loss of
the fetus [24]. Adequate immunologic responses to vaccination in pregnant women have been demonstrated in several
studies [2528]. A more recent theory proposed a shift from
Th1 to Th2 immunity. Th2 cells stimulate B lymphocyte response, increase antibody production, and suppress T lymphocyte responses, which decrease cell-mediated immunity responsible for altered responses to infections during pregnancy
in which cell-mediated immunity is important [12]. The Th2
profile, characterized by the increased levels of IL-4, IL-5, and
IL-13 is considered by some to contribute to recurrent
vulvovaginal candidiasis [29]. In essence, from the second
trimester of pregnancy until delivery, there is an antiinflammatory state. Hence, the immunologic changes and differential release of cytokines during pregnancy yields a weaker local genital tract response to Candida spp. and consequent
lack of symptoms in spite of increased frequency of
colonization [30, 31].

Pathogenesis of VVC in Pregnancy

Complications of VVC in Pregnancy

The increased risk of VVC and asymptomatic colonization in

pregnancy is likely caused by pregnancy-related factors, such
as decreased cell-mediated immunity, increased estrogen
levels, and increased vaginal mucosal glycogen production
[10]. Increased estrogen facilitates adherence of yeast to vaginal mucosal epithelial cells [2]. In addition, estrogen promotes hyphal formation and enzyme elaboration, such as secreted aspartyl proteinases and phospholipases. These virulence factors further enhance colonization [11].
Immunologic alternations during pregnancy may contribute to the altered severity and susceptibility to infections during pregnancy. As pregnancy progresses, reproductive hormone levels change dramatically and are higher than any other
time. The interplay between hormones and the immune system is complex and multifactorial [12]. High estradiol concentration enhances several aspects of innate immunity and
both cell-mediated immunity (Th2 response) and humoral
adaptive immune responses [13, 14]. Progesterone also alters
the balance between Th1 and Th2 responses [1517].
Accordingly, there is evidence that aspects of innate immunity are enhanced during pregnancy, particularly during the
second and third trimesters, hence contributing to physiologic
lower genital tract immune downregulation [18, 19]. In addition, levels of several cytokines increase that induce
phagocytic-cell recruitment or activity [18]. Conversely, the

The typical symptoms of VVC include itching, burning, redness, swelling, and discharge. Treatment of pregnant women
is primarily indicated for relief of symptoms. In particular,
recurrent vulvovaginal candidiasis adds considerably to the
discomfort of pregnancy. There is no evidence that individual
symptoms are more severe in pregnant versus nonpregnant
women.
Recently, there is some evidence that candidiasis during
pregnancy may be associated with an increased risk of pregnancy complications, such as premature rupture of membranes and poor pregnancy outcome [11, 32]. In addition,
there is some evidence that eradication of Candida in pregnancy may reduce the risk of preterm birth [33]. Roberts et al.
conducted a prospective, randomized, open-label pilot study
in which pregnant women <20 weeks of gestation with singleton pregnancies self-collected a vaginal swab. Ninety-eight
asymptomatic and Candida culture-positive women were randomized to 6 days of clotrimazole vaginal pessaries (100 mg)
or usual care (no treatment). Findings from this pilot study
support the hypothesized role of Candida in the causal pathway of preterm birth. There was a higher spontaneous preterm
birth rate in women with untreated asymptomatic candidiasis
compared to those without candidiasis (6.25 versus 2.99 %).
This was consistent with Candida colonization as a risk factor
for preterm birth. Secondly, there was a tendency toward a

Curr Infect Dis Rep (2015) 17:30

reduction in preterm birth for those women treated with clotrimazole, consistent with the report of Kiss [33].
Vaginal Candida infections causing chorioamnionitis
are rare. There are however several case reports of intraamniotic infection caused by C. albicans and C. glabrata
leading to preterm rupture of membranes or preterm labor,
and progression that could prove fatal to the fetus [34].
Chorioamnionitis has also been associated with maternal
vaginal candidal colonization, but almost only in the presence of foreign bodies such as intrauterine device or
cerclage, and prolonged rupture of membranes [34, 35].
Notably, the incidence of ascending infection is only
0.8 % [34]. C. albicans requires hyphal formation to locally
invade and cross intact fetal membranes. Access to the amniotic cavity can be achieved hematogenously from the
intervillous space or through an ascending route. Intraamniotic Candida infection may also cause systemic congenital infection, cerebral candidiasis, or fetal demise [36].
Bean et al. reported two cases of intra-amniotic C. albicans
infection that was diagnosed during previability. Both cases
had undergone cerclage placement. They were treated with
oral, vaginal, and intra-amniotic fluconazole instilled
through serial amniocenteses. Both fetuses survived without sequelae [37].
C. glabrata is the second most common Candida species.
Its pathogenicity is limited in healthy hosts, and it is considered a relatively nonpathogenic commensal of the vagina, but
vaginitis and rarely upper genital tract infection have been
described [3840]. In addition, it can cause mucosal or systemic infections in immunocompromised hosts [3841]. Ozer
et al. reported the ability of C. glabrata to cause severe
chorioamnionitis resulting in poor pregnancy outcome. They
reported two cases of chorioamnionitis occurring in pregnancies with a history of in vitro fertilization and cervical
cerclage, both resulting in fetal loss. C. glabrata was most
likely introduced into the cervix at the time of embryo transfer
and during stitching the cervix. They recommended that vaginal and in particular cervical swabs should be routinely obtained prior to cervical procedures, and appropriate treatment
should be provided to prevent these unfavorable outcomes in
pregnant women [42].
Congenital cutaneous candidiasis is a rare disorder that
results from a candidal infection acquired in utero or during
delivery. The risk of ascending infection is increased by ruptured membranes, presence of a uterine or cervical foreign
body, and a history of vaginal candidiasis. The most common
presentation is a cutaneous generalized eruption of erythematous macules, papules, and/or pustules, with a benign outcome. Oral thrush may be present at birth, and yellow-white
papules may be observed on the umbilical cord. Occasionally,
term babies with congenital candidiasis have systemic manifestations, such as pneumonia or clinical evidence of sepsis
[43, 44].

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Treatment of VVC in Pregnancy

Given the frequency of Candida vaginal colonization in
pregnant women, the majority of consultants advocate that
it is not necessary to treat asymptomatic vaginal Candida
colonization in healthy women. Nevertheless, as an exceptional approach, in Germany, it is recommended to screen
for Candida in the third trimester of pregnancy in an attempt to reduce the rate of oral thrush and diaper dermatitis
in mature healthy newborns with organisms acquired during vaginal delivery. Congenital Candida colonization has
been significantly reduced as a result of maternal treatment
[3]. However, worldwide support for this view has not been
forthcoming.
In symptomatic VVC infection, most physicians treat with
a topical imidazole, clotrimazole, or miconazole, vaginally for
7 days avoiding single-dose or short-course therapy.
Terconazole, a triazole, has a similar safety profile, but there
is less information for its use in pregnancy than for imidazoles
[45, 46]. Vaginal nystatin for 14 days is another treatment
option and has been the most popularly accepted therapy for
several decades. It is however no longer readily available,
although suppositories can be prepared by a compounding
pharmacy. Potential side effects include infrequent irritation,
burning, and redness [47].
The 2001 Cochrane review for topical treatment for vaginal
candidiasis in pregnancy included ten trials [48]. Based on
five trials, imidazole drugs were more effective than nystatin
and should be used if possible when treating symptomatic
vaginal candidiasis in pregnancy. Nystatin was as effective
as hydrargaphen in one trial, and terconazole was as effective
as clotrimazole. Single-dose treatment was no more or less
effective than 3- or 4-day treatment. Based on two trials, 7 days
was no more or less effective than treatment for 14 days [48].
A treatment course lasting more than 1 week confers no extra
benefit.
There is no evidence that one imidazole agent is any more
effective than another. It is generally advocated that pregnant
women should be offered longer courses of treatment than
nonpregnant women. There are no reliable studies on the safety or efficacy of any complimentary therapies for prevention
or cure (i.e., live yogurt) [48].
The administration of oral azoles, including fluconazole,
during the first trimester is not still recommended because
case reports have described a pattern of birth defects (abnormalities of cranium, faces, bones, and heart) after first
trimester exposure to high-dose fluconazole therapy (400 to
800 mg/day) [49, 50]. The amount of teratogenic risk is
unknown. Of note, first trimester use of a single, low dose
of fluconazole 150 mg to treat vaginal yeast infection has
not been associated with increased risk of birth defects
overall in one large study and in several smaller epidemiologic studies [5157]. In a large cohort study, there was no

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Curr Infect Dis Rep (2015) 17:30

Page 4 of 6

overall risk of birth defects associated with exposure to

cumulative fluconazole doses of 150, 300, or 350 to
6000 mg during the first trimester nor with exposure to oral
itraconazole or ketoconazole, nevertheless, an increased
risk of specific anomalies cannot be definitively excluded
[51]. Since vaginal administration is an effective alternative
to oral administration, the vaginal route is preferable to the
oral route in pregnancy, especially in the first trimester until
more data are available supporting the safety of low-dose
oral administration.
For recurrent vulvovaginal candidiasis outside of pregnancy, weekly maintenance suppressive prophylaxis is recommended [58]. In contrast to nonpregnant women, there are
no studies utilizing long-term suppressive maintenance oral
azoles for the treatment of RVVC in pregnancy. Accordingly,
most clinicians do not offer suppressive azole therapy in pregnancy and prefer to treat individual episodes to minimize exposure to medications.

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Conclusion
VVC is common in women during their reproductive years
and is a particular problem in some women during pregnancy.
Candida colonizes the vagina in up to 30 % of women in
pregnancy, especially in the second and third trimesters. Some
studies show that pregnant women were more likely to have a
symptomatic infection, while other studies found a high prevalence of asymptomatic infection only. The increased risk of
VVC in pregnancy is likely due to pregnancy-related factors,
such as immunologic alterations, increased reproductive hormone levels, and increased glycogen production. Although
evidence is incomplete, there is emerging data which suggest
that candidiasis in pregnancy may be associated with increased risk of pregnancy complications, such as premature
rupture of membranes, preterm labor, chorioamnionitis, and
congenital cutaneous candidiasis. Although most clinicians do
not treat asymptomatic Candida vaginal colonization, in some
countries, screening for vaginal Candida colonization is now
routine, and treatment in the third trimester of pregnancy potentially decreases neonatal oral candidiasis. Most clinicians
treat individual symptomatic episodes of VVC in pregnancy
with a topical imidazole vaginally for 7 days to minimize drug
exposure.

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Compliance with Ethics Guidelines

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Conflict of Interest Tina Aguin and Jack Dr Sobel have no conflict of

interest.

16.

Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by the
authors.

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