cmegyn0209_k2-1_mendling09062010

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Prenatal Diagnostics and Obstetrics
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Vaginal Candida colonization
and vaginal candidosis
during pregnancy
Werner Mendling
Vivantes Kliniken im Friedrichshain und Am Urban, Kliniken für
Gynäkologie und Geburtsmedizin, Berlin, Germany
Reviewers: Udo B. Hoyme, Erfurt, Germany
and Hanspeter Vogt, Langenthal, Switzerland
Summary
On the due date, at least 30% of all pregnant women are
colonized with yeasts, of which 90% are Candida albicans.
During vaginal delivery, vertical transmission of the yeasts
occurs in 70% to 85% of cases.Thus, the Candida carriage
rate among neonates varies between 22% and 24%, depending on the frequency of cesarean sections. Even 90% of the
healthy and mature newborns develop clinical signs of oral
thrush and/or anogenital candidosis (“diaper rash”) within
the first 12 months. Most infants, however (10%), show signs
of infection between the second and the fourth week post
partum.
High-risk newborns, especially preterm neonates, may
develop systemic candidosis. However, in contrast to the
vertical transmission in mature babies, Candida septicemia
in preterm neonates is predominantly a nosocomial infection.
Antimycotic vaginal prophylaxis for pregnant women
colonized with yeasts should be initiated in the 34th week
of gestation to significantly reduce the frequency of oral
thrush and napkin dermatitis.
Prevention of Candida septicemia in preterm neonates in
intensive care units is carried out with adequate local
and/or oral antimycotics.
96
Historical aspects
Already 100 years ago, the vertical transmission of the
yeast Candida (C.) was presumed. In 1870, the general
practitioner Haussmann suggested that the vagina was
the main source of infection for the newborn and consequently recommended prophylactic vaginal treatment for
preventing the transmission of the infectious source to the
newborn (Haussmann 1870). In 1924, Epstein, who was
working in the Karls University of Prag, pointed out that
the oral cavity of the mother was the second most important source of infection and thus also requested antimycotic treatment of the pregnant women (Epstein 1924).
In those days, the main issue was to prove the vertical
transmission during delivery. In Hamburg, Rüther, Rieth
and Koch (1958), Rieth’s PhD student Malicke (1963),
Mendling W. Vaginal ... Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 96–112 published 31.07.09 www.akademos.de/gyn © akademos Wissenschaftsverlag 2009 ISSN 1614-8533
Malicke and Rieth (1967) as well as Spitzbart from Leipzig
(1960) studied the prevalence of yeasts in pregnant women,
newborns and infants. As a conclusion, they recommended
the treatment of vaginal mycosis during pregnancy for the
protection of the newborn (Rieth [1969]:“Every newborn
has a right for a fungus free delivery” (“Jedes Neugeborene
hat einen Rechtsanspruch auf pilzfreie Geburtswege”).
In 1968, Renate Blaschke-Hellmessen was the first to prove
strain-specific characteristics within the Candida albicans
species, which allowed to draw epidemiological conclusions.
With these data, she could prove the vertical transmission
of Candida albicans from the mother to the newborn
during delivery (Blaschke-Hellmessen 1968a, 1969, 1972).
Since 1971, Johannes Schnell performed extensive investigations in the “Rheinische Landesfrauenklinik Wuppertal”
on the yeast colonization of pregnant women and the prophylactic prenatal antimycotic vaginal treatment, which is
now renown as the Wuppertal model (Mendling and
Schnell 1984; Schnell 1982).
The first monographs in German on vaginal mycosis in
pregnant and nonpregnant women were published in the
1980s (Mendling 1987; Spitzbart et al. 1981). As far as is
known to the author, there are no foreign studies or recommendations from gynecologists on the prevention of vertical transmission of yeasts during delivery. Also in Germany, this topic was not investigated or mentioned any
further, except for a neonatologist from Tübingen, who
acknowledged the existing investigations (Hoppe 1997).
However, literature on candidemia or Candida septicemia
in newborns in neonatal intensive care units is more
extensive.
Antenatal colonization of pregnant women; prerequisites
for fungal colonization, frequency and localization of
fungal colonization
Worldwide, the frequency of vaginal Candida colonization
in pregnant and nonpregnant women is comparable and
independent of climatic or ethnical influences.
Consistent with the estrogen influence on the vagina
(Dennerstein; Ellis 2007) and the existence of estrogen receptors on Candida albicans (Tarry et al. 2005), premenopausal girls and postmenopausal women are rarely colonized
with Candida in the vagina and thus rarely develop a Candida vaginitis. In average, 20% to 30% of the healthy nonpregnant and premenopausal women, 30% of the pregnant
women in the third trimester and at least 30% of the immunodeficient women are vaginally colonized (Mendling et
al. 2007; Odds 1988) (Table 1).
Table 1: Vaginal fungus colonization of pregnant women
Author
Mendling and
Schnell (1984)
Mendling
(1995)
Mendling
et al. (2007)
Location
Wuppertal and
Duisburg
Wuppertal
Berlin
Cohort
Pregnant women
on due date
Pregnant women in the 3rd
trimester
Pregnant women in the labor
room
Isolated fungal strains
(n=100%)
283
192
71
Candida albicans
77.3%
77.5%
94.4%
Candida glabrata
7.7%
7.5%
2.8%
Other species of
Candida*
11.9%
0.25%
2.8%
Further species*
3.1%
* C. guilliermondii, C. krusei, C. parapsilosis, S. tropicalis, C. kefyr, C.
famata
** Rhodotorula rubra, Saccharomyces cerevisiae,Trichosporon species
types, Geotrichum candidum
However, the vaginal colonization individually varies from
time to time: in one longitudinal cohort study carried out
with 1248 asymptomatic nonpregnant young women over
a one-year period, 70% were colonized in one or more
examinations, but only 4% had positive cultures on all
examinations, i.e. every three months (Beigi et al. 2004).
Methodologically similar case studies around the world
suggest that the average colonization rate of 30% has not
changed much during the last 100 years (Mendling et al.
2007; Odds 1988; Schnell 1982). A bacterial vaginosis, which
affects approximately 20% within the second and third trimester, usually suppresses Candida colonization (Mardh et
al. 2002). Apparently, the physiological alterations in the
vagina during pregnancy favor the proliferation of Candida
albicans, as Candida glabrata is not found as often as in
nonpregnant or postmenopausal women (Mendling et al.
2007).
Several decades ago, Bland et al. (1937) performed a unique
study, which would not have been allowed nowadays out
of ethical reasons, in which they discovered that the risk for
developing a Candida induced vaginitis is notably higher in
colonized pregnant women than in colonized nonpregnant
women. In this study, pregnant and nonpregnant women
were infected with yeasts, which led to a vaginal mycosis in
80% of the pregnant but only 33% of the nonpregnant
women.
97
Parity, age, nationality and preeclampsia did not represent
additional risk factors (Schnell 1982).
Although the supplementation of Candida albicans and
Candida glabrata with lochia discharge in vitro favors their
proliferation (Neumann and Kaben 1972), the vaginal yeast
colonization decreases after delivery without treatment
(Spitzbart 1960, Schnell 1982), an observation that Haussmann already made in 1870. Post partum, the surface and
intermediary cells are immediately shed together with the
lochia. This, in turn, washes off the free and the intercellular and intracellular fungi. Simultaneously, glycogen supply
decreases. In postmenopausal healthy women who do not
receive hormone supplementation, the genital yeast colonization is only 5% to 10% and thus relatively low.
2
98
The typical symptoms of a vaginal candidosis (Fig. 1) are
vaginal rash, soreness, burning, dyspareunia and dysuria.
However, these symptoms alone do not allow for a reliable
differentiation between the different causes of vaginitis.
On the other hand, it is unlikely that the patient suffers
from vaginal candidosis if there is no rash or pruritus
(Anderson and Cohrsen 2004). In contrast to a bacterial
vaginosis, the discharge does not have a foul smell. The
small labia may be swollen and red and especially in recurrent cases, burning superficial fissures in the epithelium
may appear. If that mycosis spreads to the vulva and the
perianal and/or intestinal region, we differentiate between
a pustular, an eczematoid (Fig. 2) or a follicular (skin) candidosis (Mendling and Seebacher 2008).
Apart from the vaginal fungus colonization, the oral and
intestinal colonization of pregnant women is of great importance. Here, Candida albicans exists just as often as in
the vagina. Candida albicans is equally prevalent in the oral
cavity of pregnant women than in nonpregnant women
with an average of 30% to 50%. Alongside the vagina, the
oral cavity of the mother is a typical contamination source
if there is intensive body contact to the newborn.
Clinical signs and symptoms
Compared to nonpregnant women, pregnant women
suffer more often from pruritus within the introitus, even
though no yeasts can be found (Mendling et al. 2007).
Due to the estrogen induced vaginal milieu, premenopausal women frequently suffer from a primary vaginal candidosis that can subsequently spread to the vulva. Postmenopausal women usually develop vulva candidosis or candidosis of the intercrural folds. In nonpregnant women, the
symptoms usually develop prior to menstrual bleeding, as
the glucose level of the vagina is highest after ovulation
(Eckert et al. 1998; Mendling 2006).
Figure 1: Candida-albicans vaginitis in the 14th week of pregnancy
In approximately 90% of cases, the typical symptom is
pruritus. However, it is not reliable as only 35% to 40% of
women with genital pruritus really suffer from a vaginal
candidosis (Anderson 2004). We could confirm this finding
in one of our own investigations carried out with more
than 600 pregnant women (Mendling et al. 2007).
Figure 2: Eczematoid Candida-albicans vulvitis (and vaginitis)
In more than 90% of pregnant, asymptomatically colonized
women and in women with acute vaginal candidosis prior
to menopause, Candida albicans is the responsible pathogen (Mendling et al. 2004; Mendling and Seebacher 2008;
Sobel 2007). Non-albicans-types, especially Candida
glabrata, rarely occur in pregnant women and, in nonpregnant women, usually only appear in the late premenopausal or perimenopausal phase (Fidel et al. 1999; Mendling
1981; Sobel 1998; Spinillo et al. 1995). A Candida-parapsilosis
vaginitis (Nyirjesy et al. 2005) and the rare Saccachromycescerevisiae vaginitis have almost never been found
(Mendling 2006; Sobel 1993).
A Candida cervicitis is an extremely rare incident that is
referred to as a rarity in literature. A Candida cervicitis can
lead to an intrauterine candidosis of the fetus with chorioamnionitis, whether or not the amniotic sac is intact.
Between 1925 and 1985, Roger et al. (1986) only found 32
cases in the world’s literature. Schnell (1982) found 34 cases
since 1958 and added his own observations. An intrauterine
Candida infection is favored by the existence of an intrauterine pessary and can cause preterm delivery (Donders et
al. 1990).
Czeizel concluded that the increased preterm delivery rate
was only due to Candida colonization. As clotrimazole also
eliminates gram-positive cocci (personal message, 2008),
the initial hypothesis was that clotrimazole eliminated the
causative agents of the bacterial vaginosis and thus reduced preterm delivery. In a prospective randomized preterm delivery prevention study carried out in Vienna, Kiss
et al. (2004) found a significant reduction in preterm delivery after vaginal treatment with clotrimazole in the first
trimester. Teratogenicity has never been observed after
clotrimazole therapy during pregnancy (Czeizel and
Rockenbauer 1999).
Transmission of Candida to the newborn and its consequences (symptoms and diseases) in healthy, mature newborns
The studies of Blaschke-Hellmessen (1969) in Dresden and
Schnell (1986) in Wuppertal showed that vertical transmission during delivery from women colonized with Candida
in the vagina takes place in 70% to 85% of cases (Table 2).
Well-founded suspicion of these connatal Candida infections of the newborn is only appropriate if, during delivery
or within the first 24 hours, the newborn presents with
maculopapulous skin efflorescences and/or severe signs of
infection in combination with a positive yeast culture from
the lesions or the blood of the newborn.
Table 2:Transmission of Candida to the newborn during delivery
(Blaschke-Hellmessen et al. 2006)
Does vaginal Candida colonization favor preterm delivery?
In 50 women with a massive Candida-albicans colonization
of the vagina, Schnell (1982) could not find a histologically
evident infiltration of the lower eggpole. However, in 10
cases, he found inflammatory cells.
In a more recent study, Candida albicans was isolated in 5
out of 773 women with preterm labor but an intact amniotic
sac and in 4 out of 625 women with premature rupture of
the membranes by amniocentesis (Chaim et al. 1992).
In earlier studies, Schnell (1982) could not prove any differences in the frequency of preterm rupture of the membranes in 399 vaginally colonized women and 1088 noncolonized women in their last trimester. However, recent
studies suggest that Candida albicans can favor preterm
delivery. Albeit with a different intention, a retrospective
study carried out with 38000 women in Hungary proved
that vaginal treatment with clotrimazole in the first trimester significantly reduced preterm delivery rates (Czeizel
et al. 2004; Czeizel and Rockenbauer 1999; Hay and Czeizel
2007).
Frequency
Pregnant women with antenatal
vaginal Candida colonization
30%
Of these women, Candida was
transmitted to the newborn during
delivery by
70% to 85%
This then resulted in an infection
rate of the newborn during delivery
of
21% to 25%
Before the first bath, 22% to 24% of the newborns were
colonized with Candida either on the skin, the oral cavity or
the rectum (Table 3). Afterwards, the Candida colonization
of the mature and healthy newborns and the preterm
babies that had underwent vaginal delivery dropped to below 10% within the first days of life (Table 4). Table 5 additionally illustrates that the yeast flora in the oral cavity and
on the skin of the newborn is identical to the vaginal flora
of the mother, which is also apparent in the frequency of
Geotrichum candidum (plant pathogen, found in milk and
cheese products) (Blaschke-Hellmessen 1969) (see Table 5).
These more than 40-year-old findings were confirmed by
Blaschke-Hellmessen in an orientating study in 1995 (see
Table 6). During the first days and weeks of life, the digestive system and the body surface begin to be colonized
with yeast-like fungi, which usually have pathogenic potential. The majority of mature newborns (10% to 13%)
develop symptoms in between the second and the fourth
week of life.
Table 3: Colonization by Candida albicans on the first day of life
(Blaschke-Hellmessen et al. 2006)
Year
Children
Number
Prior to the
(n = 100%) first bath
1966
1976
1986
1970
1973
1979
Newborn babies
Newborn babies
Newborn babies
Preterm babies
Preterm babies
Preterm babies
200
468
89
225
175
590
After the first
bath
21.5%
Table 5: Percentage of the appearance of yeasts in pregnant women
ante partum and newborns post partum; in total, 200 mother-child
couples; 200=100% (Blaschke-Hellmessen 1969)
Species
Pregnant women
Oral cavity
Newborns
Rectum Vagina Oral cavity
Skin on
the neck
C. albicans
37.5%
27.5%
24.0% 19.7%
15.5%
C. krusei
1.9%
2.8%
2.8%
1.4%
0.9%
C. kefyr
4.2%
0.5%
0.5%
0.9%
0.5%
C. glabrata
–
0.7%
1.9%
1.9%
0.9%
Geotrichum
candidum
11.7 %
32.6%
6.1%
5.2%
3.3%
12.6%
23.6%
10.2%
12.5%
6.4%
Table 4: Frequency of yeasts in the newborn post partum and during
the first four days of life (Blaschke-Hellmessen et al. 2006)
Yeasts in
Examined
children: 200=100% general
Candida
albicans
Oral cavity
Post partum
On the 1st day of life
On the 2nd day of life
On the 3rd day of life
On the 4th day of life
33.3%
26.6%
22.3%
25.3%
23.2%
19.7%
7.3%
2.7%
4.3%
2 .8%
Skin on the neck
Post partum
On the 1st day of life
xx
2On the 2nd day of life
On the 3rd day of life
On the 4th day of life
23.9%
13.0%
14.6%
8.7%
10.9%
15.6%
4.7%
3.8%
3.8%
4.9%
Rectum
On the 3rd day of life 19.1%
On the 4th day of life 19.5%
12.4%
9.8%
Table 6: Frequency of yeasts in the digestive system in newborns and
infants (Blaschke-Hellmessen 1998)
Number
Yeast colonization in total
Oral
cavity
Stool
Cohort
Healthy
newborns,
two weeks old,
living with the
family
100
16.0%
8.5%
15.2%
High-risk
newborns in
an intensive
care unit
68, of which
long-term
interns: 2
38.3%, of which 24.3%
long-term interns:
50% colonized on
day of admittance,
erworben),
23% nosocomial
colonization)
30.6%
After four weeks, almost all children that are colonized
with Candida albicans during delivery have clinical signs of
infection (see Fig. 3,Table 7). The children develop oral
candidosis (oral thrush, Fig. 4), which usually becomes
evident as a rash of the tongue and the oral mucosa with
the development of white fungal plaques. In addition, an
anogenital skin candidosis develops after passage through
the gastrointestinal system. The children start to drink less
and become ill as the mouth and the perianal region become sore and painful.
Percent
100
80
Yeasts in total
60
40
Candida albicans
20
Clinical candidosis
Post 3. T
partum
1 M 2–3 M 6 M
9M
1J
1.5 J
2J
3J
T: Day, M: Month, J: Year
Figure 3: Frequency of yeasts and clinical candidosis in newborns,
babies and infants. The percentage refers to a total of 200 newborns
and 400 babies and infants, respectively (Schwarze, in BlaschkeHellmessen et al. 2006).
Table 7: Frequency of oral thrush and skin candidosis dependent on
the child’s age
Year of
examination
Child’s age (days)
6
10 14 21
28
49
70
Schwarze
et al. (1976)
1976
3.0
13.0 9.5
4,5
Schnell ( 1984)
1982
Authors
1.4
11.5
6.1
10.7
Figure 5: Anogenital candidosis (from: Mendling 2006, by courtesy of
the Springer Verlag, Heidelberg)
However, also a reinfection of the child from the mammilla,
which can be asymptomatically colonized with Candida
albicans, is possible. The mother, in turn, rarely suffers from
a cutaneous candidosis as a consequence of the oral thrush
of the breastfed baby (Chetty et al. 1980).
For the first time ever, Blaschke-Hellmessen (1969) identified the origin of isolated Candida-albicans strains from
mother and child by detecting strain-specific characteristics.
Immediately after birth, all strains found in the newborn
were identical with those in the mother. The typification of
the Candida-albicans isolates was done by strain-specific
proteinase and lipase activity. Ever since, the vertical transmission in mature healthy newborns is considered as
proven.
These more than 40-year-old findings are today confirmed
by modern molecular biology methods. For instance, my
own working group used the DNA fingerprint method by
polymerase chain reaction on Candida albicans strains
from couples living in a sexual relationship (Mendling et al.
1998). Rodero et al. (2000) accomplished the typification of
Candida tropicalis isolates by southern blot hybridization
and he thus clarified the transmission of the fungus in
neonatal intensive care units.
Preterm babies – risk of nosocomial infections
Similar to immunocompromised adults, preterm neonates
are especially endangered when it comes to systemic Candida infections.
101
Figure 4: Oral thrush (from: Mendling 2006, by courtesy of the
Springer Verlag, Heidelberg)
The symptoms and laboratory findings of a Candida septicemia are unspecific, and often only the pathologist diagnoses the pathogen. This has been confirmed by autopsy
reports from previous years of the Charité Clinic Berlin
(Koch et al. 2004) and the University Clinic Greifswald
(Schwesinger et al. 2005).
In an intensive care unit, Blaschke-Hellmessen (1998) found
Candida colonization in 38% of the high-risk newborns and
50% of the so-called “long-term interns” were colonized.
Half of these children were already colonized when admitted to the intensive care unit, most probably during
delivery. The remaining children were initially free of yeasts
(23% in total) but were then nosocomially colonized while
in hospital (see Table 6).
In a prospective study carried out with 150 preterm neonates and their mothers in the context of a dissertation, we
could prove that a Candida septicemia in preterm babies in
the intensive care unit usually is not due to the vertical
transmission of the yeast but rather has a nosocomial
source (Laskus et al. 1998). The most important risk factors
are low birth weight and intensive care measures, especially catheter and antibiotherapy. Oral prophylaxis, in this
case with the polyene preparation nystatin, was life saving
for these children (see Table 8).
Two relatively recent dissertations from Würzburg (Elstner
2003; Meyer 2004), that are based on the mycological expertise of the neonatologist Frank-Michael Müller (today
working in Heidelberg) (Müller et al. 2001), confirm that
28% of the newborns below 1500 g birth weight are colonized by Candida and, with a probability of 2% to 7%, develop
Candida septicemia. Children below 1000 g birth weight
are colonized in 41% of cases and their risk of developing
Candida septicemia is 10%. If the birth weight is below
800 g, 20% will develop Candida septicemia, which is lethal
in 25% to 50% (up to 75%) of cases. In 70% of cases, Candida
albicans is the pathogen, in 23% it is a non-albicans species
and in 3% of cases, the mould Aspergillus fumigatus causes
the infection. Lethality is highest if Candida albicans is involved (Table 9). Similar data are available from foreign
countries.
Table 9: Results from an analysis of candidemia in neonatal intensive
care units
Table 8: Influence of nystatin prophylaxis on the morbidity and
mortality of preterm babies (Laskus et al. 1998)
Preterm
babies
Oral nystatin
prophylaxis,
in case of
antibiotherapy
Below 1000 g
1 000 to 1 499 g
1 500 to 2 500 g
No*
(n = 6)
No*
(n = 17)
No*
(n = 50)
Yes
(n = 18)
Yes
(n = 24)
Yes
(n = 45)
Authors
Müller (2001)
Tortorano et al.
(2001)
Kiraz et al.
(2000)
Countries
Germany,
ESPED study
2001
Europe, ECMM
working group
Turkey
Years
2 years
1997 to 1999
1997 to 2000
123**
278
100
16
5
5
1
2
2
1
1
74
35
3
5
86
11
12
122
6
(4)
1
Cases/episodes 36*
n
%
n
%
n
%
n
%
n
%
n
%
Candida
colonization
4
66,6
1
12.5
3
17.6
0
0
5
10
1
2.2
Candida
infection
2
33,3
0
0
0
0
0
0
0
0
0
0
Death caused 1
by Candida
infection
16,6
0
0
0
0
0
0
0
0
0
0
2
102
Candida
albicans
parapsilosis
tropicalis
glabrata
krusei
famata
kefyr
inconspicua
lusitaniae
guilliermondii
(Aspergillus
fumigatus)
10
2
14
Candida
species: 13
* Here, nystatin prophylaxis was only administered if one of the
weekly fungus cultures from mouth, ear, stool or urine was positive.
A study by Romaniuk et al. (2002) in St. Petersburg illustrates these findings as they identified 25% newborns
with systemic candidosis in an intensive care unit.
* Birth weight: < 750 g: 70 cases; 751 to 1000 g: 39 cases; 1001 to 1 500g:
17 cases; > 1500 g: 10 cases
Mortality: C. albicans: 25%; Non-albicans: 17 %; (Aspergillus fumigatus: 75%)
** Birth weight: average 875 g; gestational age: average 26 weeks
The risks for the mother are vaginal delivery and a prolonged prenatal therapy with antibiotics. The more severe
neonatal risks are the preterm rupture of the membranes,
the duration of an antibiotherapy and, of course, the
maturity measured as the birth weight or the pregnancy
duration.
Per year, in 1000 newborns born in one clinic, an average of
five are preterm births with a birth weight below 1000 g
and approximately six to eight below 1500 g. Thus, without
prophylaxis, one case per year will develop candidemia or
Candida sepsis.
Mastitis puerperalis - caused by Candida?
The correlation between mastitis puerperalis and Candida
has hardly been studied. In 1975, Johannes D. Schnell and
the author of this article systematically investigated the
colonization of the lactating mamma with Candida. From
200 lactating mothers, a smear culture of the mammilla
and the surrounding skin was carried out just before the
baby was breastfed for the first time and three days later.
The culture mainly revealed Staphylococcus epidermidis,
only in one case a single colony of Candida albicans was
found in the first smear. However, cultures of the second
smear three days after the initiation of lactation were
positive for Candida albicans on both breasts in 13 of 200
cases (6.5%). There were no clinical signs of infection of the
mammilla. The examination of the children revealed that
9 children out of the 13 colonized mothers had a clinically
and culturally confirmed oral thrush caused by Candida
albicans (Schnell 1982). Thus, the mother’s mammilla was
colonized from the child’s mouth, which, in turn, was
colonized by the Candida strain colonizing the mother’s
vagina.
So far, mycosis of the breast has only been found in a few
cases. A cutaneous candidosis of the mammilla of a lactating mother as a consequence of an oral candidosis or a
newborn has also only scarcely been described (Chetty et
al. 1980).
Until now, it was thought that yeasts would only rarely
appear in the mother’s secretion of nonpregnant women
and that candidosis of the mammary gland is extremely
rare (Opri 1982).
For their metabolism, yeasts require iron. They possess socalled siderophores, which “steal” iron from the host’s cell.
Although lactoferrin contains iron, the yeasts cannot utilize
it. In contrast, the lactoferrin contained in the breast milk
can inhibit the growth of Candida albicans and thus prevent the Candida infection of the mammary gland. However, it also alters the in vitro proliferation, i. e. culturing of
Candida from a breast smear. The supplementation of iron
in the mother’s milk in vitro increases the Candida proliferation by two to threefold (Morill et al. 2002).
More than 30 years ago, the Dresden working group around
Renate Blaschke-Hellmessen successfully cultured Candida
from breast milk by inhibiting the proliferation of the bacteria by adding Raulin solution, which also contains ferrosulphate (Blaschke-Hellmessen 1977). From 1968 until 1989,
Candida albicans was yearly found in 5.2% to 8.5% in more
than 37000 smears (Blaschke- Hellmessen et al. 1991).
Consequently, referring to recent studies, the addition of
iron to breast milk containing lactoferrin can cause clinical
signs of a skin infection of the mammilla or Candida mastitis. In a prospective study carried out with 100 lactating
healthy mothers, breast smears were taken two weeks post
partum and the mothers were observed between the second and the ninth week. Candida colonization was associated with a high predictability of clinical signs that
suggest the diagnosis Candida mastitis. The clinical signs
were scalding and shiny skin in the mammilla and areola
region combined with a pinching pain in the breast or a
burning skin sensation in the mammilla areola area
(Francis-Morill et al. 2004).
Accordingly, in one case, mother and child were successfully treated with systemic fluconazole, after the failure of
local antimycotic therapy. However, the cultural confirmation was missing (Chetwyns et al. 2002).
In a prospective study carried out in Melbourne with 61
breastfeeding mothers that were suffering from pain in
the mammilla, there was a statistically significant correlation between the presence of Staphylococcus aureus and
the fissures in the mammilla, but also the presence of
Candida albicans on the mammilla and in the extracted
milk (p=0.01) (Amiv et al. 1996).
103
However, due to the increasing interest in breastfeeding,
combined with information and management (WHO/UNICEF-Initiative,“Nationale Stillkommission” – national
breastfeeding committee), the interest of physicians in
breastfeeding has also increased. This also explains, why
(finally) mycological issues have arisen.
Further prospective studies will have to be carried out in
order to clarify the open questions. It is possible that Candida albicans as a cause for puerperal mastitis or infected
mammillae plays a more important role than we thought.
Prenatal antimycotic prophylaxis and antimycotic therapy
during pregnancy
Antimycotic prophylaxis
The discussion on prenatal oral thrush prophylaxis started
more than 100 years ago. It is closely connected to the
names Berg (1846), Haussmann (1870), Epstein (1924),
Malicke (1958), Spitzbart (1960), Blaschke-Hellmessen
(1968b), Rieth (1979), Schnell (1982, 1986) and Mendling
(Mendling and Schnell 1984, Mendling and Spitzbart 1994/
2008).The objective is the elimination or reduction of Candida colonization of the vagina towards the end of pregnancy but prior to delivery by the administration of antimycotic preparations.
Referring to extensive studies by Schnell (1982), the prophylactic vaginal administration of clotrimazole from the
34th week of pregnancy onwards reduces the frequency of
Candida colonization from 24.4% to 7.1% and from 26.8% to
9.0% (Table 10). In the newborns, the vertical transmission
of Candida drops from 18.6% to 3.2%.
Table 10: Reduction of yeast colonization in mothers and children with
a six-day prophylaxis (Schnell 1984)
Mother-childpairs (n=100%)
607
630
Six-dayprophylaxis
Reduction of
yeasts of
Unfortunately, regardless of our objections, the recommendation was not corrected in August 1987 but, instead, completely removed. It is regrettable that the German health
system only finances diseases but not their prophylaxis.
The same goes for the prevention of preterm birth by pH
measurement and native preparations in the first trimester.
Recommendations for the diagnostics
In order to appropriately leverage the prenatal prophylaxis
of pregnant women, the “recommendations for antimycotic therapy of vaginal yeast colonization in pregnant women for the prevention of vulvovaginal mycosis of newborns” (“Empfehlungen zur antimykotischen Therapie der
vaginalen Hefepilz-Kolonisation der Schwangeren zur Verhütung von Kandida-Mykosen beim Neugeborenen”) on
behalf of the “Arbeitsgemeinschaft für Infektionen und
Infektionsimmunologie in der Gynäkologie und Geburtshilfe (AGII)” were developed in 1994 (Mendling and Spitzbart 1994) and by now have been updated (Mendling and
Spitzbart 2008). In this recommendation, testing for yeasts
in the vagina of pregnant women by culturing is recommended from the 34th week of pregnancy onwards (Table 11).
Mother Fungus
vaginal colonization
Child post- 3rd day 5th day
partum
No prophylaxis
antimycotic on the last medical checkup”. However, this recommendation was incorrect and neither in agreement
with the committee of the “Kassenärztlichen Bundesvereinigung” nor with the few experts. The main mistake was
that no prior culturing was required. Thus, any woman
would have received an antimycotic, regardless of whether
she was colonized or not. In addition, the “last” check-up
before birth can be difficult to schedule.
26.8%
26.8%
Table 11: Recommendations for the antimycotic therapy of vaginal
yeast colonization of pregnant women for the prevention of candidosis in the newborn (Mendling and Spitzbart 2008)
18.6% 12.7%
9.0%
9.0%
3.2%
4.4%
66%
83%
64%
66%
xx
These results illustrate the advantages for mother and
child and we can estimate the treatment to be cost-effective for the investor.
• From the 34th week of pregnancy onwards: culturing of the fungi
from the vagina on Sabouraud glucose or Kimmig agar (the native
preparations from vaginal secretions in asymptomatic yeast
colonization only have a sensitivity of 50% to 60%).
• Intravaginal therapy with adequate polyene or azole antimycotics
in case of a positive fungal culture – independent of the clinical
symptoms. As the one-dose therapy has got the same effectiveness,
it should be preferred before the other therapy forms. Treating the
partner is not necessary.
• In case of a risk for preterm birth, the fungus culture and, if applicable, the therapy should occur early in order to protect the
especially endangered newborns during preterm vaginal delivery.
The efforts to perform prenatal antimycotic prophylaxis in
pregnant women were first legally reflected in the alteration in the motherhood guidelines in December 1985.
Originally, the recommendation was “a one-off dose of an
The native preparation from the vaginal discharge is not
recommended, as even an experienced examiner would
only detect yeasts in approximately 50% of cases in asymptomatically colonized pregnant women with a 400-fold
magnification.
Measures of prophylaxis
In case of a positive culture, an intravaginal antimycotic
drug should be administered. Treatment of the partner is
not necessary. If, after the antimycotic therapy, yeasts persist, the proliferation until delivery is usually insignificant
(Schnell 1986), which further decreases the neonatal infection risk. In a dissertation, Römeth (1993) could prove the
effectiveness of the prophylaxis by making a great effort
of visiting mothers and their newborns at home. The study
was carried out in Wuppertal and became known as the
“Wuppertal model”. It was confirmed in a study carried out
in Bielefeld with 850 mothers and their children (dissertation Sutyadi 1986, quoted by Schnell 1986).
These findings from the 1980s were also published in Great
Britain and the USA, due to the publications of Schnell.
However, they were never followed up further.
The antimycotic prophylaxis was carried out with adequate
polyene (nystatin, amphotericin B) or azole antimycotics
(e. g. imidazoles, such as clotrimazole, econazole nitrate,
miconazole nitrate, fentikonazole nitrate). An intravaginal
one-off dose or three-day therapy with imidazoles is preferential due to the improved compliance with similar
effectiveness. If there is a risk for preterm birth, the fungal
culture and the administration of an antimycotic drug
should be individually initiated earlier. The above mentioned recommendations have also been included in the
guidelines for vulvovaginal candidosis (Mendling and
Seebacher 2008) that have been consented by the AGII
together with the “Deutschsprachige Mykologische Gesellschaft” (DMyG) and the “Deutsche Dermatologengesellschaft” (DDG).
Culturing of the fungus and the subsequent antimycotic
prophylaxis are no longer mandatory referring to the
maternity guidelines. Thus, it is the gynecologist’s decision
to point out the possibility of antimycotic prophylaxis.
For the above mentioned reasons, we consider antimycotic
prophylaxis to be useful and thus recommend the review
of recent studies, especially on the frequency of neonatal
Candida infections after prophylaxis (until now, the studies
focus on the neonatal Candida colonization after prophylaxis). In addition, calculations proving the cost effectiveness
are still missing.
Therapy of vulvovaginal candidosis during pregnancy
While the asymptomatic Candida colonization only has got
to be treated from the 34th week onwards for the protection of the newborn, a vulvovaginal candidosis presenting
with pruritus, discharge and rash has got to be treated at
all stages of pregnancy. Usually, the treatment of the asymptomatic partner is without benefit for the woman.
Imidazole preparations (e. g. clotrimazole, econazole,
miconazole) are slightly superior compared to nystatin,
regarding the cure and recurrence rate during pregnancy
(Coleman et al. 1998).
In addition, there is evidence that the several-day-therapy
is more effective than a one-dose treatment of Candidaalbicans vulvovaginitis during pregnancy (Sobel 2007). The
administration of oral triazoles (e. g. fluconazole, itraconazole) is not permitted in Germany, due to the risk of heart
and skeletal system malformations after a long intake of
400 mg to 800 mg during early pregnancy.
Ciclopiroxolamine has got a similar cure rate than imidazoles. However, it is only available as a six-day therapy
(attention: do not confound inimur myko® with inimur®,
which contains nifuratel, which is effective against trichomoniasis, bacteria and Chlamydia).
Antimycotic prophylaxis and the consequences for
preterm babies
In general, it is not the gynecologist’s task to treat sick
newborns or preterm babies. However, healthy mature
newborns often remain in the obstetric care unit together
with their mothers. In addition, the fact that during delivery,
obstetric interventions can increase the risk for infections
in the newborn justifies the gynecologist’s interest in this
field. The following recommendations mostly come from
pediatricians.
The goal of antimycotic prophylaxis for preterm babies (as
well as for sick mature newborns) is to either prevent the
colonization of yeasts or fungi, especially Candida albicans,
to eliminate the colonization from the digestive tract or to
at least reduce it below the tolerance level of less than 103
to 104 yeast cells per gram stool. This should then prevent
the invasion and the hemato-lymphogenic dissemination.
The administration should be initiated prior to the invasive
growth of the fungi and the risk of infection of the organs.
Without doubt, there is a smooth transition between prophylaxis and early therapeutic effect of antimycotics.
105
Antimycotic drugs with effect on the intestine have to meet
specific requirements.They need to have a local effect, be
non-absorbable, have no side effects, should not affect the
physiological bacterial flora of the gut and have to reach a
sufficient concentration in the digestive tract.These requirements correspond most to the properties of the polyenes
nystatin and amphotericin B, which undergo limited or no
absorption after oral administration.
Both drugs have a fungistatic effect and are fungicidal in
high concentrations. While passing through the stomach
and the intestine, the polyenes are partly inactivated and
excreted with the stool (Blaschke-Hellmessen et al. 1991;
Blaschke-Hellmessen and Schwarze 1994). The excretion
begins on the second, at the latest on the third day of administration and usually persists during administration.
Two to ten days after termination of treatment, excretion
sinks below detection level.
Referring to existing publications, the general oral thrush
prophylaxis for mature newborns is not recommended for
preterm babies. Instead, only the targeted use in high-risk
newborns in inpatient treatment is recommended, as it is
thought to reduce infant mortality.
At the University Clinic Dresden, where expertise has
gathered over the last 40 years due to the cooperation
between the neonatologist Schwarze and the mycologist
Blaschke-Hellmessen, the oral administration of nystatin
has proven itself (Schwarze et al. 1995; Schwarze and
Blaschke-Hellmessen 1998). The incidence of systemic
candidosis (septicemia and meningitis) in very early preterm
babies only amounted to 1%. Nystatin prophylaxis is indicated in the presence of at least three risk factors for invasive mycosis (Table 12). The corresponding dosage is outlined in Table 13. Experience shows that the oral cavity is
the most difficult site to keep fungus-free. Thus, it should
additionally be treated with a nystatin suspension or a
miconazole oral gel.
Table 12: Prophylactic oral administration of antimycotic agents
Preparation
Miconaxx
Patients
Daily dose
Newborns 4 x 25 g
Administration after
the meal
Oral gel
zole
Nystatin
Amphotericin B
Newborns:
• < 1 500 g • 3 x 100 000 IE
• > 1 500 g • 3 x 150 000 IE
As a suspension (in addition,
painting of the mouth cavity with
the same suspension 6 times
daily)
Table 13: Comparison of the effectiveness of oral administration of
nystatin suspension and amphotericin B in high-risk newborns with a
disseminated intestinal candidosis (Schwarze et al. 1995)
Patients
Nystatin
(300 000 or
450 000 IE/day)
Nystatin
(300 000 or
450 000 IE/day)
High-risk newborns
(n=100%)
Birth weight (range)
48
48
1 687 g
(680 to 3 680 g)
32.9 weeks
(26 to 41 weeks)
1 867 g
(800 to 4 070 g)
33 weeks
(25 to 42 weeks)
7 = 14.6%
16 = 53.3%
41 = 85.4%
1 4 = 46.7%
Gestational age (range)
Success rate during a
10-day administration
Children with multiply
positive fungal stool
cultures (2 to 6 specimens)
Children with negative
stool cultures or only one
positive stool culture
(1 specimen)
Nystatin and amphotericin B have a strong influence on
the yeast colonization of the intestine. At the time of the
first positive stool sample, usually 24 to 48 hours after
therapy initiation, the presence of fungi in the intestine is
greatly reduced compared to the initial colonization. Thus,
as long as polyenes are administered, the concentration of
yeasts in the stool sinks below detection level. In some
cases, yeasts are still detectable in the stool in low quantities. For instance, in premature preterm babies with a birth
weight below 1500 g, the yeasts can persist for a longer
period than in children with a higher birth weight and a
more advanced gestational age (Blaschke-Hellmessen et al.
1991). Similar observations have been made for patients in
the neutropenia phase receiving antileukemic drugs (Finke
1990).
Another possibility is fluconazole (i. e. 6 mg/kg oral every
third day or, from the second to the fourth week: every second day). In a prospective, randomized, double blind study
over a period of 30 months carried out in 100 preterm
babies with a birth weight below 1000 g, treatment with
fluconazole for six weeks significantly reduced the colonization with Candida from 60% to 22% and the rate of invasive Candida infections from 20% to 0%. However, the
mortality rate remained the same (Kaufmann et al. 2001).
Newborns:
• < 1 500 g • 4 x 0.2 ml (80 mg) As a suspension
• > 1 500 g • 4 x 0.4 ml (160 mg)
Neonatologists have not decided whether the prophylaxis
in preterm babies is best done with local intestinal nystatin
or a systemic fluconazole treatment (Austin and Darlow
2002; Kaufmann et al. 2001). In any case, a risk-adapted
antimycotic prophylaxis is recommended.
It is certain that, apart from the effect of the antimycotic
drug, the immune defense of the patient plays an important role in suppressing the yeasts in the gastrointestinal
tract. A permanent elimination of yeasts in the intestine is
almost impossible. Thus, a long-term administration of
polyenes is necessary if there is a high risk for invasive
Candida infections.
The effectiveness of daily oral doses of nystatin on the elimination or reduction of yeasts in the intestinal tract has
been proven. In patients receiving nystatin, 85% of the
patients had a negative or only one positive stool culture
compared to a significantly lower success rate of only 47%
in patients receiving amphotericin B (p=< 0.01). Thus, nystatin should be the first choice, also because the nephrotoxic
amphotericin B can sometimes be absorbed in preterm
babies (Blaschke-Hellmessen and Schwarze 1991).
Assuming that the goal of oral antimycotic prophylaxis in
preterm babies is the radical reduction of fungal colonization of the intestine below detection levels, the prophylaxis
can be considered as being effective. However, fungal infections that do not originate from the intestine but from another disseminating focus cannot be prevented with oral
polyene preparations. Thus, many neonatologists prefer
the administration of fluconazole. Considerung the currently improved diagnostic, therapeutic and prophylactic
possibilities, every attempt should be made to protect premature or sick newborns from the consequences of an invasive life-threatening Candida mycosis.
CME Prakt Fortbild Gynakol Geburtsmed Gynakol
Endokrinol 2009; 5(2):96–112
Keywords
Vagina, Candida, pregnancy, neonatal candidosis
215
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Prof. Dr. med. Werner Mendling
Vivantes Kliniken im Friedrichshain und Am Urban
Kliniken für Gynäkologie und Geburtsmedizin
Landsberger Allee 49
10249 Berlin
Germany
Prof. Mendling studied medicine in Mainz and Düsseldorf.
After his final exam in 1974 and the promotion in 1975 in
Düsseldorf, he worked in the “Rheinischen Landesfrauenklinik und Hebammenlehranstalt Wuppertal-Elberfeld”
(since 1985 known as the “Kliniken St. Antonius gGmbH”)
from 1976 until 1995. He habilitated in 1994 on the immunological detection of vulvovaginal mycosis in Witten/Herdecke. From 1995 to 2000, he was the chief physician of the
“Klinikum Frankfurt/Oder”. In 1995, he continued with
further postdoctoral research, and in 2000 was appointed
lecturer at the Humboldt University (Charité) Berlin. Since
2000/2001, he is the head physician of the “Vivantes
Kliniken für Gynäkologie und Geburtsmedizin der Kliniken
Am Urban und im Friedrichshain Berlin”.
Conflict of interest
The author declares that there is no conflict of interest as
defined by the guidelines of the International Committee
of Medical Journal Editors (ICMJE; www.icmje.org).
Manuscript information
Submitted on: 02.04.2009
Accepted on: 07.05.2009
110
CME
Vaginal Candida colonization and vulvovaginal
candidosis during pregnancy
Question 1
The percentage of women who are colonized by
Candida during the third trimester is approximately:
a. 10%
b. 30%
c. 50%
d. 70%
e. 90%
Question 2
The medically relevant Candida species are:
a. Candida (C.) albicans, C. gasseri, C. krusei,
C. tropicalis
b. C. albicans, C. glabrata, C. tropicalis, C. parapsilosis
c. C. albicans, C. glabrata, Saccharomyces cerevisiae
d. C. albicans, C. tropicalis, C. kefyr, C. lusitaniae
e. C. albicans, C. glabrata, C. krusei, Aspergillus
fumigatus
Question 3
The clinical signs of a vulvovaginal candidosis with
C. albicans are:
a. unambiguous, if the patient suffers from pruritus
at the introitus and has a white curd-like vaginal
discharge
b. vulvovaginal rash, whitish vaginal discharge with
no offensive odour and a varying intensity and
consistency, usually with a neutral pH
c. postmenstrual burning discomfort in the introitus and an increased pH.
d. genital pruritus, vulvovaginal rash, dyspareunia
and a fishy discharge.
e. painful lesions in the introitus with rash and
lymph node swelling in the groin
Question 4
The treatment of vulvovaginal candidosis during
the first trimester with clotrimazole:
a. reduces the risk for abortion
b. increases the risk for preterm birth
c. reduces the risk for preterm birth
d. should not be administered vaginally, but orally
e. should be postponed until the third trimester, in
order to prevent candidosis of the newborn
Question 5
Of 100 mature, healthy newborns:
a. approximately 21 to 25 are colonized by various
Candida species during vaginal delivery
b. approximately 3 to 10 suffer from Candida
septicemia
c. approximately 10 of the female newborns will
develop vulvovaginal candidosis
d. approximately 85 to 90 will develop “oral thrush”
e. approximately 1 to 2 are born with a systemic
Candida infection
Question 6
Out of all healthy mature newborns, in which vertical transmission of Candida albicans occurs during
delivery, the following percentage develop oral
thrush and/or anogenital candidosis:
a. 1% during the second to the fourth week,
b. 5% during the second to the fourth week,
c. 10% to 20% during the sixth month
d. 50% during the first 12 months but with a peak of
5% in between the fourth and the sixth week
e. almost 100% within the first 12 months with a
peak between the second and the fourth week.
Question 7
Preterm babies are especially endangered:
a. The risk for developing oral thrush and anogenital
candidosis is 20% if they have a birth weight
below 1500 g.
b. The risk for developing oral thrush and anogenital
candidosis is only increased if the mother is a
carrier.
c. The risk for developing Candida septicemia is only
increased if the birth weight is below 1000 g.
d. The risk for developing Candida septicemia is 10%
if the birth weight is below 1000 g.
e. The risk for a Candida septicemia is only increased
if the species is C. glabrata.
Question 8
From the 34th week of pregnancy onwards, the
intravaginal administration of an antimycotic drug
in an adequate dosage is indicated:
a. in case of a positive fungal culture, in order to
prevent the postpartal delevopment of oral
thrush or anogenital candidosis in mature
newborns after vaginal delivery
b. in case of a positive fungal culture, in order to
prevent the postpartal development of a Candida
septicemia in mature newborns after vaginal
delivery
c. in all women, in order to prevent the postpartal
delevopment of oral thrush or anogenital
candidosis in mature newborns after vaginal
delivery
d. in all women, in order to prevent the postpartal
development of a Candida septicemia in mature
newborns after vaginal delivery
e. in case of a positive fungal culture and a high
probability for preterm birth, in order to prevent
the postnatal development of Candida septicemia
111
1212
Question 9
Nystatin is
a. a polyene antimycotic, which undergoes little or
no absorption after oral administration and is
thus used for the superficial treatment of oral
intestinal candidosis
b. a polyene antimycotic, which undergoes absorption after oral administration and is thus used for
oral and intestinal candidosis as well as for
treating vulvovaginal candidosis
c. a polyene antimycotic, which is not absorbed and
is effective for the treatment of yeasts as well as
dermatophytes
d. an azole antifungal drug, which is absorbed after
oral intake and effective against dermatophytes,
yeasts and molds
e. a polyene and an azole antimycotic
Question 10
The following substances are effective treatments
against vulvovaginal candidosis:
a. Nystatin, amphotericin B, clotrimazole, nifuratel
b. Nystatin, amphotericin B, clotrimazole, ciclopiroxolamine
c. Clotrimazole, ciclopiroxolamine, nifuratel,
nystatin
d. Clotrimazole, miconazole, econazole nitrate,
metronidazole
e. Garlic extract, yogurt, tee tree oil, lactobacillus

cmegyn0209_k2-1_mendling09062010

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