Disclaimer: This Risk Newsletter summarizes the information available at the time of it’s creation. The information presented below is meant for educational purposes only. Patients should always consult their health care provider for updated information and clinical care. If you have further questions regarding the information presented below, please contact a health care provider in your area.
The services provided by Illinois Teratogen Information Service, including this RISK newsletter, are funded by the Illinois Department of Public Health and supported by Northwestern University Medical School and Northwestern Memorial Hospital in Chicago, Illinois.
ILLINOIS TERATOGEN INFORMATION SERVICE
Teratogen
Newsletter
Antifungal use during pregnancy is common because
pregnant women are more susceptible to fungal infections. In addition, pregnancy is more commonly
associated with more serious systemic fungal infections, such as mycoses, that
require treatment. There are three
types of treatment that can be used for fungal infections: topical, vaginal and
systemic/oral. The following review
provides a summary of current data on the use of each type of fungal medication
in pregnancy (over the counter medications and prescription medications are
abbreviated in the sub-headings as (OTC) and (P) respectively).
TOPICAL THERAPY:
The use of antifungals in the topical treatment of
infections of hair, skin and nails is common.
Prescription and over the counter treatments are available for a variety
of infections. To date, no topical antifungal treatments have been shown to be
teratogenic during human pregnancy.
Imidazoles are active in treating ringworm, tinea
versicolor and cutaneous candidal infections.
Animal studies have suggested teratogenicity of some imidazoles in high
oral doses, but not with topical use.
Topical agents are absorbed less by the body when compared to oral
preparations, and have not been found to be teratogenic (King et al 1998). Jick (1999) reported on 492 women exposed to
various topical azoles (ketoconazole, miconazole and econazole). A relative risk of 2.1 (95% CI 0.7-6.8) was
not statistically significant for an increased risk of congenital
malformations, when compared to matched controls. There is some suggestion that ketoconazole and miconazole could
inhibit testosterone synthesis in utero, which could potentially inhibit
genital development of a male fetus.
However, this has not been documented in any controlled studies. Surveillance data from the Michigan Medicaid
study reported by Rosa et al (1987, did not find an increased risk for
congenital malformations with miconazole or clotrimazole use during pregnancy.
AMPHOTERICIN
B-(P)
Topical
use of amphotericin B has shown minimal absorption through the skin. Limited
human surveillance data do not indicate any harm to mother or fetus, but
relative safety is still unknown (King et al, 1998).
VAGINAL THERAPY:
Inflammation of the vagina is extremely common in
the general population. Symptoms
include soreness, irritation, and discharge.
Differential diagnoses (excluding sexually transmitted diseases) for
symptoms of vaginal irritation include candida vulvovaginitis (VVC), bacterial
vaginosis (BV), trichomoniasis, and atrophic vaginitis. VCC is one of the most common fungal
infections, affecting 50% of women by age 25.
Some of the more common treatment options for the above-mentioned
conditions are described below; all of which are over the counter (OTC) with
the exception of terconazole.
COLTRIMAZOLE-
(OTC) Gyne-Lotrimin̉Mycelex̉
Clotrimazole
is an OTC medication used to treat VVC.
Clotrimazole is minimally absorbed (3-10%). The Michigan Medicaid
Surveillance study reported on 1086 pregnancies exposed to clotrimazole during
the first trimester (King et al, 1998).
There were 74 pregnancies with a birth defect (RR=1.09, 95% CI 0.9-1.4),
and 112 spontaneous abortions (RR=1.34, 95% CI 1.1-1.7). These data suggest a slight increase in
spontaneous abortions, but no increase in birth defects, with first trimester
exposure to clotrimazole. Clotrimazole
is thought to be safe during the second and third trimesters of pregnancy (King
et al, 1998). Czeizel et al (1999)
studied the possible teratogenicity of clotrimazole for topical and vaginal
therapy using a case-control surveillance study of 18,515 exposed pregnancies
during three specific time intervals; first month, second and third month, and
fourth through ninth month. Using
32,804 controls, they determined that clotrimazole use was not associated with
an increase in congenital anomalies (OR=0.72, 95% CI 0.54-0.95). Further research has indicated that the use
of clotrimazole may have a protective effect on preterm delivery. Czeizel and Rockenbauer (1999) determined
that the use of clotrimazole during pregnancy significantly reduced the
incidence of preterm births (t=8.86, P,0.001).
These authors suggest that because clotrimazole effectively treats
maternal infection, its use during pregnancy is indicated to eliminate maternal
infection associated with prematurity.
MICONAZOLE-(OTC)
Monistat̉
Miconazole (monistat̉) is one of the most
commonly used over the counter medications for yeast infections. It is used topically (see above) and
intravaginally for VVC treatment.
Vaginal use has shown minimal systemic absorption (1.4%) (King et al,
1998). The Michigan Medicaid surveillance (Rosa et al 1987) reported on 2236
exposed pregnancies and 144 birth defects.
These data do not support a significant increase in fetal malformations
above the general population (RR=1.02, CI 0.9-1.2). The same surveillance study
reported a slightly significant increase in spontaneous abortions in women who
were prescribed miconazole 120 days before pregnancy loss, when compared with
full term deliveries (RR=1.36, CI 1.1-1.6).
Lack of controlled studies on the safety of miconazole use during
pregnancy, however, does not provide an accurate estimate of potential risk.
NYSTATIN -
Mycostatin̉
Nystatin
is a polyene antifungal and is available over the counter. Vaginal preparation is the only type of
application available due to toxicity by IV or oral administration. Nystatin is poorly absorbed systemically
after topical or mucosal application.
Specific use of nystatin has not been studied during pregnancy. Animal studies do not show an increased in congenital
malformations (Rosa et al, 1987).
Surveillance studies by the Collaborative Perinatal Project and
Collaborative Drug Surveillance program did not find an increase of congenital
malformation with first trimester use.
Rosa et al (1987) reported data from the Michigan Medicaid study on
women who received prescriptions for nystatin during the first trimester of
pregnancy. Of 848 pregnant women, 66
deliveries were linked to birth defects.
Their results were not statistically significant for an increase in
birth defects over the general population
(RR=1.25, CI 0.97-1.6). Surveillance
by the Michigan Medicaid study did not show a significant increase in
spontaneous abortions (SAB) in women who were prescribed nystatin 120 days
prior to pregnancy loss when compared to full term deliveries (RR=0.87, CI
0.6-1.2). Although these data do not
suggest a risk to human pregnancy, the lack of controlled human studies makes
it difficult to establish relative safety.
Butoconazole
–(OTC) Femstat̉
Butoconazole
is minimally absorbed systemically (5.5%).
Clinical trials suggest relative safety with use during the second and
third trimesters of pregnancy (King et al, 1998). However, these data are not from controlled studies and
therefore, butoconazole should be used with caution during pregnancy.
Tioconazole-(OTC)
Vagistat̉
Tioconazole
is minimally absorbed systemically (5%-16%).
Clinical trials suggest relative safety with use during the second and
third trimesters of pregnancy (King et al, 1998). However, these data are not
from controlled studies and therefore, tioconazole should be used with caution
during pregnancy.
Terconazole-
(P) Terazol̉
Tioconazole
is thought to have negligible systemic absorption. There are currently no human data to determining safety during
pregnancy. (King et al, 1998)
SYSTEMIC THERAPY:
Systemic (oral/IV) antifungal medications are used to treat
serious fungal infections, such as meningitis.
Cryptococcal meningitis is an infection that apparently does not cross
the placenta (Chen et al, 1996), but failure to treat can compromise maternal health
and thus the health of the fetus.
Because of their toxicity, use of systemic antifungals during pregnancy
is limited to life-threatening infections. There is relatively little data on
the more potent systemic antifungals. However, the triazole class of systemic
antifungals (including fluconazole and itraconazole) are less toxic
alternatives and therefore have been studied more commonly in pregnant
women. This review will concentrate on
oral and IV preparations of systemic antifungal medications that have been well
studied during pregnancy. This comparison will highlight differences in
toxicity and how they affect pregnancy.
TRIAZOLES
ITRACONAZOLE –(P) (Oral-
Sporanox̉)
Itraconazole is another azole preparation
that is related to ketoconazole and fluconazole and is used orally to treat
fungal infections. Jick (1999) reported
on 88 women exposed to oral itraconazole; however, dose was not reported. When compared to matched controls,
itraconazole exposed women had a relative risk of only 0.6 (95% CI 0.2-1.6) of
having a baby with congenital anomalies.
Other data on the use of oral itraconazole during pregnancy is limited
to case reports, which have also failed to suggest an increased risk for fetal
birth defects.
FULCONAZOLE-(P) (IV and Oral -
Diflucan̉) Triazole
used to treat systemic fungal infections (candidiasis, cryptococosis,
coccidioiidomycosis and meningitis) penetrates the CNS and is present in high
concentrations in the cerebral spinal fluid (CSF). Animal studies have shown teratogenic effects when fluconazole is
administered at high doses (20-40X the normal human dose), including structural
and craniofacial anomalies. Lee et al (1992) reported 3 patients exposed
prenatally to fluconazole. These patients
showed a pattern of Antley-Bixler-like malformations. Pursley et al (1995) reported 3 patients (2 siblings) exposed to
high oral doses throughout the first trimester (400mg/day for first 24 weeks,
400mg/day for first 4 months, 800mg/day for first 7 weeks). These patients exhibited craniofacial,
skeletal, and cardiac anomalies. One of the three patients was reported to have
the previous diagnosis of Antley-Bixler syndrome. They concluded that fluconazole is teratogenic in humans and it
is likely that other related azoles are also teratogenic. Kyrieckos and Bartley (1997) reported a single patient with fetal
exposure to fluconazole in the first 9 weeks gestation [400mg/day (0-4/5 weeks
gestation), 800mg/day (4/5- 9 weeks gestation)] for a maternal meningitis
infection. Amphotericin B 50mg
(3x/week) was also given over the next three months with fluconazole treatment
resuming at 22 weeks (1200mg/day). This
patient also presented with Antley-Bixler-like phenotype. Although this pregnancy was complicated with
many other medications besides the two antifungals, Kyrieckos and Bartley
(1997) concluded that fluconazole is teratogenic capable of producing
Antley-Bixler-like phenotype when women are exposed to high doses for long
duration in early pregnancy.
Antley-Bixler phenotype includes the following features: brachycephaly,
depressed nasal bridge, dysplastic ears, frontal bossing, midfacial hypoplasia,
pear shaped nose, proptosis, large anterior fontanelle, long philtrum,
craniosynostosis, choanal stenosis/atresia, femoral bowing, radiohumeral
synostosis, femoral fracture, thin ribs, multiple contractures, long palms and
fingers, camptodactyly, rockerbottom feet, cardiac defects, cleft palate and
early death.
Masrroiacovo
et al (1996) performed a prospective cohort study from the Italian Teratogen
Information Service (ITIS). Of the
women exposed to fluconazole, 90.7% was for oral treatment of vaginal
candidiasis. The majority of the women were exposed to single low doses (oral)
of fluconazole (median 200mg) during the first trimester. The only significant difference between
exposed and control groups was an increased therapeutic abortion (TAB) rate in
the exposed group. With these results they concluded that single low doses of
fluconazole during the first trimester are not associated with an increased
risk for SAB, stillbirth or congenital anomalies.
Sorensen et al (1999) preformed a
retrospective study of 165 women who had received fluconazole prescriptions
just before or during pregnancy, and compared them to 13,327 women that did not
receive prescriptions. Their study found no increase in congenital
malformations with single exposures to fluconazole before conception or during
pregnancy. However, this study has many
confounding variables primarily receiving a prescription does not ensure that
the medication was taken. This is a
large source of bias in the study.
Jick
(1999) reports on 234 women of which 92% were exposed to single 150 mg doses of
fluconazole. When compared to 492
matched controls, a relative risk of 1.1 (95% CI 0.4-3.3) for congenital
abnormalities was calculated. Three
of their patients exposed to high doses exhibited limb deformities that
suggested a pattern of malformations.
These data suggest possible teratogenicity of fluconazole at high dose.
KETOCONAZOLE-(P)
(oral - Nizoral̉)
Numerous problems have been reported with the use of
systemic ketoconazole during pregnancy.
It has been shown to be teratogenic and embryotoxic at high doses in
animals, with additional data to suggest prolonged gestation. Ketoconazole crosses the placenta and is
thought to inhibit gonadal and adrenal steroid synthesis in humans. It has been suggested that ketoconazole use
during pregnancy could inhibit sexual differentiation, although to date there
are not human data to prove such an association (King et al 1998). McGregor and Pont (1990) indicated that
therapeutic doses (200mg and 400mg/day) have not been associated with a major
block in steroid synthesis.
Ketoconazole is also used to treat Cushing
syndrome. Two case reports of treatment
for Cushing’s are the only data on human exposure during pregnancy. No adverse outcomes were reported. In Amado et al (1990) treatment was
administered during the third trimester, when the sex of the fetus was already
identified. In the second case report
(Berwaerts et al, 1999) the patient
received ketoconazole therapy from 1-3 weeks and 7-37 weeks of pregnancy. The pregnancy ended in a vaginal delivery at 37 weeks of a normally
developed male infant. From this case
report, Berwarts et al (1999) argue that ketoconazole is safe to administer
during pregnancy. However, lack of data
still make it difficult to establish safety.
MICONAZOLE-(NP)
(IV)
OTHER SYSTEMICS
METRONIDAZOLE (P)
Metronidazole is an antimicrobial agent that is primarily used to treat
protozoan infections. There has been
controversial evidence regarding its use during pregnancy. However, more recent epidemiological studies
have led to more conclusive support for its use during pregnancy. Previously, it was hypothesized that
metronidazole could increase the risk for birth defects and possibly for cancer
due to its mutagenic capabilities.
Olson Robbie et al (1983) reviewed the use of metronidazole in obstetrical
practices. Their literature
substantiated that metronidazole crosses the placenta and is found in high
concentrations in fetal tissue and amniotic fluid. Their study reports on 597 women exposed to oral metronidazole
during pregnancy for a treatment period of 7 to 10 days. When compared to 283 untreated controls,
there were no significant differences in stillbirths or prematurity. There was no evidence to suggest teratogenicity. Their paper suggested further studies on the
carcinogenesis of metronidazole were needed.
Burtin et al (1995) did a meta-analysis on the safety of metronidazole
use during pregnancy. They reported
on 7 studies (6 prospective of 253
first trimester exposed women and 1 retrospective of 1083 exposed women) in
which there was no increased risk for teratogenicity with metronidazole use
during pregnancy (OR=0.93, 95% CI, 0.73-1.18). Czeizel and Rockenbauer (1998) did a case-control study on the
use of oral metronidazole during the various times of pregnancy (first month,
second to third month and fourth to ninth months). Their data did not suggest an overall increase in congenital
abnormalities between cases and controls
(OR=1.12, 95% CI, 0.83-1.50) with second and third month exposures. However, certain birth defects were found at
a slightly higher incidence in the case populations, and exposure throughout
pregnancy did show a slight increase in congenital anomalies (OR=1.25, 95% CI,
1.11-1.42). Cleft lip with or without
cleft palate and neural tube defects were increased with first month exposures,
poly/syndactyly, anal atresis/stenosis, and hydrocephaly were increased with
second and third month exposures and cardiovascular congenital abnormalities
were increased in the case population with exposures between the 4th
and 9th months. These data
can be explained by embryology. The
most critical timing for heart development is between the 3rd and 9th
weeks. The authors did suggest that due
to the retrospective nature of the study, these findings were possibly due to
confounding factors. Caro-Paton et al
(1997) did a meta-analysis on the
teratogenicity of metronidazole. They
looked at all cohort and case-control studies that estimated a risk of
congenital malformations after metronidazole exposure during pregnancy. They concluded that first trimester exposure
to metronidazole does not significantly increase the risk for congenital
abnormalities (OR=1.08, 95% CI, 0.9-1.29) .
The nature of this study did not allow for analysis of specific birth
defects. In general, data do not
suggest an overall increase in congenital anomalies with metronidazole use
during pregnancy. However, even though
some studies examined second and third trimester exposures, there are no data
regarding the risk for prematurity, low birth weight or stillbirth associated
with metronidazole use during that period of pregnancy.
The question of increased cancer risk in
children exposed to metronidazole during pregnancy has been studied by
Purushottam et al (1998). They studied
a retrospective cohort of children under the age of 5. In their study they did not find an
increased risk for tumor development (leukemia, neuroblastoma, CNS tumors, and
other cancers) in children exposed prenatally to metronidazole when compared to
non-exposed controls. Further analysis
of the carcinogenicity of metronidazole has not shown an increase in risk for
tumor formation in women followed 20 years after treatment for vaginal
trichomoniasis (Beard et al; 1998).
These findings were based on 771 women, and did not show evidence for
mutagenic properties of metronidazole treatment.
Similarly
to clotrimazole, metronidazole has also been thought to be protective against
preterm labor be induced by maternal infection. In a placebo controlled trial by
McDonald et al (1997), pregnant women using metronidazole had a
significantly reduced risk for preterm labor when compared to the placebo group
in two categories: women who previously had experienced preterm labor, and
women with previous preterm labor that also had bacterial vaginosis. This study did not find a significant
difference between treatment and control populations in women without any
history of preterm labor (infection or no infection).
FLUCYTOSINE-(P)
Flucytosine is limited to the treatment of yeast
infections, and resistance is developed rapidly following treatment. Data suggest that flucytosine is teratogenic
in rats at doses less that the normal human dose (mg/kg basis). Flucytosine is known to cross the
placenta. Case reports of use during
the second and third trimesters have not shown adverse outcomes (only 3
reports). Due to its mechanism of
action, flucytosine has the potential to cause congenital defects in humans and
is therefore contraindicated in pregnancy (King et al 1998).
GRISEOFULVIN-(P)
Griseofluvin is used to treat ringworm. It has been reported to be embryotoxic in
animals and crosses the placenta in humans.
There is some suggestion of an association between first trimester
exposure and an increased incidence of conjoined twins (2 case reports), but
further epidemiological studies failed to support these preliminary findings.
Other data regarding the use of griseofluvin during pregnancy is limited to
case reports. These limited findings
specifically reported by the FDA might be associated with an increased risk for
miscarriage, but these data have not been confirmed by controlled studies.
However, due to limited information, it is suggested that griseofluvin use be
avoided during pregnancy (King et al, 1998).
TERBINAFINE-(P)
To date there is minimal data on the use of
terbinafine for fingernail and toenail infections during pregnancy. Animal studies reveal that there is no
evidence for fetal harm. However, there have been no controlled studies on
human use during pregnancy (King et al
1998).
POTASSIUM
IODIDE –(P)
Oral iodides are used to treat cutaneous infections.
In general, iodides are thought to be contraindicated in pregnancy because they
have been associated with congenital goiter that can be fatal in newborns (King
et al 1998).
AMPHOTERICIN B -(P)
Amphotericin
B is a polyene antifungal that has been used for more than 30 years, with
numerous adverse effects (transient azotemia, febrile reactions, shaking
chills, nephrotoxicity, thrombophlebitis, electrolyte disorders and anemia). Amphotericin B is used to treat numerous
types of infections including: histoplasmosis, blastomucosis, cryptococcosis,
coccidioidomycosis, visceral leishmaniasis, and cryptococcal meningitis. Oral preparations of amphotericin B are
still the chosen antifungal for severe infections. Amphotericin B is known to cross the placenta and enter the fetal
circulation. It is also available in
topical form for less severe infections but is minimally absorbed by the
skin.
Oral/IV
formulations of amphotericin B are commonly prescribed during pregnancy. King et al
(1998) reviewed its use during pregnancy, and 26 additional cases of
amphotericin B use during pregnancy. Because of the toxicity of amphotericin B,
adverse maternal reactions were commonly reported which included: anemia, acute
nephrotoxicity, fever, chills, headache, nausea and vomiting. Fetal effects that were most commonly seen
included: anemia, low birth weight, microcephaly, transient acidosis, increased
serum creatine (SCr) levels, respiratory failure, transient maculopapular
rash. Their review of the data
concluded that Amphotericin B is the
drug of choice for life threatening fungal infections during pregnancy. Its use in human pregnancy has not shown
consistent adverse fetal effects.
Maternal toxicity is common and pregnant women should be closely
monitored if taking amphotericin B.
SUMMARY:
It
is important to weigh the risks and benefits of any drug usage during
pregnancy. In the context of antifungal
medications, it is necessary to consider the potential risks to both mother and
fetus if the infection goes untreated. Current literature does not address the
risks of an untreated infection. If an infection worsens during pregnancy, a
higher dose may be needed, which may affect the fetus. In general, there is a higher rate of
relapse with certain infections when a woman is pregnant (especially candidal
vaginitis). This can be important to consider when treating fungal infections
in pregnant women. Overall, data differs on the various types of antifungals available. Choosing one that is favorable for treating
the particular infection while considering the potential risks to the fetus is
critical when managing the treatment of a pregnant woman.
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