Download Antifungal Therapy During Pregnancy

1151
Antifungal Therapy During Pregnancy
Coleman T. King, P. David Rogers, John D. Cleary, and
Stanley W. Chapman
From the Section of General Internal Medicine, Department of
Medicine, School of Medicine, University of Georgia, Augusta, Georgia;
and the Department of Clinical Pharmacy Practice (School of
Pharmacy), Department of Microbiology (School of Medicine), and
Division of Infectious Diseases (Department of Medicine), The
University of Mississippi, Jackson, Mississippi
Careful consideration of the benefit to the mother and the risk to the fetus is required when
prescribing antifungal therapy in pregnancy. Imidazoles are considered safe as topical therapy for
fungal skin infections during pregnancy. Nystatin is minimally absorbed and is effective for vaginal
therapy. Although vaginal use of the imidazoles is probably safe during the later stages of pregnancy,
their systemic absorption is higher than when applied to the skin. The systemic antifungal drug
with which there has been the most experience in pregnancy is amphotericin B. There have been
no reports of teratogenesis attributed to this agent. There is evidence to suggest that fluconazole
exhibits dose-dependent teratogenic effects; however, it appears to be safe at lower doses (150
mg/day). Ketoconazole, flucytosine, and griseofulvin have been shown to be teratogenic and/or
embryotoxic in animals. Iodides have been associated with congenital goiter and should not be used
during pregnancy.
Prescribing medications to pregnant women requires a delicate balance between the mother’s need for treatment and the
potential risk of damage to the fetus, including congenital malformations, adverse effects, and the health of the pregnancy
itself. Although the dictum ‘‘No drug should be considered
absolutely safe during pregnancy’’ cannot be questioned, most
practitioners find this impractical. There are instances in which
pregnant women require medications. Fortunately, scientific
data and reports on clinical experience are available to provide
guidance when drug therapy during pregnancy is necessary.
The use of antifungal medications in pregnancy is addressed
in this report. References were selected by a MEDLINE search
of the English-language literature from 1966 to the present,
including reference citations and relevant articles.
Pregnant women are susceptible to the same fungal infections as are nonpregnant women, and in some cases their risks
are increased. Candidal vaginitis, for example, is common in
nonpregnant patients, but it is more common, more frequently
refractory to therapy, and more likely to relapse in pregnant
patients [1]. Pregnancy is also associated with more systemic
and serious fungal infections. Coccidioidomycosis is believed
to disseminate more frequently in pregnant females [2]. Other
systemic mycoses occasionally occur in pregnancy and present
therapeutic dilemmas in which two lives are involved.
Received 15 January 1998; revised 16 June 1998.
Reprints or correspondence: Stanley W. Chapman, Division of Infectious
Diseases, Department of Medicine, School of Medicine, Jackson, Mississippi
39216-4505.
Clinical Infectious Diseases 1998;27:1151–60
q 1998 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/98/2705–0007$03.00
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A number of publications are available to aid clinicians in
choosing the safest drug therapy for a pregnant patient [3 –
5]. In 1980, the U.S. Food and Drug Administration (FDA)
published definitions for pregnancy risk categories [6]. As
shown in table 1, categories A through D and X are assigned
in accordance with a product’s estimated potential harm to a
fetus. These designations provide a grading scale by which to
rate a product’s relative risk of use in pregnancy. They are
derived from pooled data from various pharmacological investigations, animal studies, and clinical experience. Although not
absolute, these categories serve as general guidelines and are
listed in most major texts and in individual-product monographs. It should be noted that manufacturers are not required
to provide pregnancy risk categories for drugs marketed before
December 1983.
Topical Therapy
Fungal infections of the skin, hair, and nails are a common
clinical problem. The majority of these infections are caused
by dermatophytes, although yeasts such as Malassezia furfur
and Candida albicans are also frequently implicated [7]. These
infections are usually responsive to topical medications when
a small area of the skin is involved. Extensive cutaneous disease
and/or hair or nail involvement, however, often requires a
course of oral agents such as ketoconazole, fluconazole, itraconazole, griseofulvin, or terbinafine for resolution. Unfortunately, therapy with both topical and systemic antifungal agents
is associated with high relapse rates.
Numerous topical antifungals are available in both prescription and nonprescription preparations. Chemical compounds
such as ammonium derivatives, chlorinated or iodinated compounds, phenols, and dyes have been used over the years, but
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Table 1. Classification of prescription drugs by the U.S. Food and
Drug Administration, according to risk in pregnancy.
Pregnancy risk
category
A
B
C
D
X
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fetus have not been fully elucidated and the bases that serve
as vehicles for these agents contain a variety of chemical compounds.
Description
Controlled studies of women failed to demonstrate a risk
to the fetus in the first trimester, and the possibility of
fetal harm appears remote.
Either animal studies do not indicate a risk to the fetus
and there have been no controlled studies of pregnant
women, or animal studies have indicated fetal risk but
controlled studies of pregnant women failed to
demonstrate a risk.
Either animal studies indicate a fetal risk and there have
been no controlled studies of women, or there are no
available reports of studies of women or animals.
There is positive evidence of fetal risk, but there may be
certain situations where the benefit may outweigh the
risk (e.g., life-threatening or serious diseases for
which other drugs are ineffective or carry a greater
risk).
There is definite fetal risk, according to studies of
animals or humans or on the basis of human
experience, and the risk clearly outweighs any benefit
in pregnant women.
NOTE. This table is adapted from the Federal Register [6].
little is known regarding their safety in pregnancy. Some of
the commonly used topical antifungal agents are shown in
table 2. The imidazoles (clotrimazole, econazole, miconazole,
oxiconazole, ketoconazole, and sulconazole) are active against
ringworm, tinea versicolor, and cutaneous candidal infections
[8]. Although some imidazoles have been shown to be teratogenic or embryotoxic at high oral doses in the rat [9 – 13],
they are generally considered safe for topical use in human
pregnancy [3, 4]. The topical dose is a small fraction of the
dose used in these animal studies, and systemic absorption of
imidazole compounds is minimal when they are applied to
human skin.
The polyenes (amphotericin B and nystatin) likewise are
minimally absorbed from skin, but because of a narrower spectrum of activity, they are of limited benefit in the treatment of
ringworm [14, 15]. Terbinafine cream is effective for treatment
of tinea pedis, tinea corporis, and tinea cruris. However, there
are no data regarding systemic absorption of topical terbinafine
in humans, and there have been no adequate, well-controlled
studies of the use of this agent by pregnant women. Although
other agents such as naftifine, tolnaftate, ciclopirox, and haloprogin provide excellent activity against dermatophytes, they
have higher systemic absorption after local application than do
the imidazoles, and data regarding their use in human pregnancy are lacking [16 – 18]. None of these topical preparations
have been implicated as a cause of fetal or maternal harm in
human pregnancy. Indiscriminate use in pregnancy should be
avoided, however, as the effects of these drugs on the human
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Vaginal Therapy
The available intravaginal antifungal preparations are listed
in table 3. Imidazoles and nystatin are the mainstays of topical
therapy for candidal vaginitis [19 – 26]. These agents have been
widely used in pregnancy, and both retrospective and prospective comparative trials suggest that they are reasonably safe.
Most manufacturers, however, caution against their use during
the first trimester. With the exception of terconazole, all of the
topical azole preparations are now available over the counter.
Nystatin, a polyene antifungal discovered in 1949, represents
one of the first antifungal agents isolated [27]. The drug is not
absorbed after ingestion and is toxic when given intravenously.
Therefore, nystatin is used only topically. Systemic absorption
of nystatin after topical or mucosal application is negligible
[19]. To our knowledge, there have been no reports of animal
or human teratogenesis with this agent.
Extensive data for intravaginal application of nystatin during
the first trimester of human pregnancy are available. Rosa et
al. found no increased risk of congenital malformations in 842
first-trimester exposures [28]. The National Institutes of Health
Collaborative Perinatal Project reported a slight increased risk
of congenital malformations in a series of 142 women with
first-trimester exposures, but this was attributed to concurrent
Table 2. Topical antifungal agents.
Agent
Risk category
Nonprescription
Clioquinol
Clotrimazole
Miconazole
Naftifine
Nystatin
Tolnaftate
Undecylenic acid
Prescription
Amphotericin B
Butoconazole
Ciclopirox
Econazole
Haloprogin
Ketoconazole
Oxiconazole
Sulconazole
Terbinafine
Terconazole
Tioconazole
Triacetin
NA
B
C
B
B
NA
NA
B
C
B
C
B
C
B
C
B
C
C
NA
NOTE. NA Å manufacturer has not assigned agent to a risk category.
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Table 3. Topical vaginal antifungal agents.
Drug
Risk
category*
Systemic
absorption*
Embryotoxic
in animals*
Nystatin
Miconazole
A
C
Negligible
1.4%
No data
Yes
Clotrimazole
Butoconazole
Terconazole
Tioconazole
B
C
C
C
Up to 3% – 10%
5.5%
5% – 16%
Negligible
Yes
Yes
Yes
Yes
Human trials
Safe in all trimesters
Possibly increased risk of spontaneous
abortion
Safe in second and third trimesters
Safe in second and third trimesters
Safe in second and third trimesters
No data
NOTE. None of the oral or systemic azoles have received approval by the U.S. Food and Drug Administration
for use in any trimester of pregnancy.
* Product monograph information from [19 – 24], unless otherwise specified.
tetracycline therapy [29]. The Group Health Cooperative of
Puget Sound study found no increased risk of fetal malformations or other adverse effects with 225 first-trimester exposures
from 1977 to 1979 [30] and with 176 exposures from 1980 to
1982 [31].
In addition, numerous trials have compared nystatin with
other agents for use in pregnant women [32 – 41]. The largest
such study, that of McNellis et al., included 53 first-trimester
exposures and 191 exposures in later trimesters and showed
no increase over the expected number of fetal or neonatal
deaths [42].
Imidazoles are the other commonly used topical agents for
treatment of yeast vaginitis. In the studies comparing imidazoles to nystatin, imidazoles have uniformly superior cure rates
and lower relapse rates [32, 33, 35, 37, 38]. In a study of
volunteers, 1.4% of the topical vaginal dose of miconazole was
recovered in the urine and feces after 96 hours [25]. Although
animal studies utilizing high doses of this drug have demonstrated both embryotoxicity and prolongation of gestation [20],
miconazole has been used frequently and, for the most part,
safely in human pregnancies.
Weisberg reviewed studies in which a total of 471 patients
had used miconazole during pregnancy without adverse maternal or fetal effects [43]. McNellis et al. demonstrated the overall
safety of this product in 291 pregnant women, 43 of whom
were in their first trimester [42]. The study by Rosa et al. found
an increased risk of birth defects, with a relative risk of 1.02
(95% CI, 0.9 – 1.2); however, this was not statistically significant and this study has been the subject of some debate [28].
Fewer data are available concerning the use of clotrimazole
in pregnancy. Vaginal absorption is estimated at 3% – 10% of
the topically applied dose [26]. Animal studies have shown
decreases in litter size and number of viable young with highdose exposure [21] but no adverse effects of vaginal therapy
during pregnancy. Rosa et al. showed no increased risk of
adverse fetal effects in 1,012 first-trimester exposures [28].
Other studies in pregnancy with considerably fewer patients
have supported this finding [32, 33, 37 – 39, 44 – 46].
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Trials with limited numbers of patients have shown no adverse fetal or maternal effects linked to the use of butoconazole
in the second and third trimesters of pregnancy [22, 47]. Terconazole is absorbed vaginally to some degree in humans and
may cross the amniotic membrane. One study reported a 2.9%
incidence of birth defects in 1,167 first-trimester exposures [3].
Insufficient published data are available regarding the use of
tioconazole and econazole in human pregnancy [48].
In summary, the only data against use of the imidazoles in
pregnancy are those of Rosa et al. [28] regarding miconazole
during the first trimester. The other imidazoles have been less
well studied, and few or no data are available. Although the
Centers for Disease Control and Prevention previously recommended only nystatin for therapy during the first trimester,
their most recent recommendations support the use of azoles —
specifically, butoconazole, clotrimazole, miconazole, and terconazole — for vaginal therapy in all trimesters [49].
Systemic Therapy
Systemic antifungal agents have traditionally been regarded
as toxic medications, and their use in pregnancy has been limited to life-threatening fungal infections. Thus, very little information is available on the use of these drugs in pregnancy. In
contrast to the vaginal antifungals, no large-scale trials have
been performed, and any existing data on the use of these
agents in human pregnancy are from isolated case reports.
Amphotericin B
The systemic antifungal drug with which there has been the
most experience in human pregnancy is amphotericin B [50 –
71]. This polyene antifungal was first demonstrated to have
antifungal properties in 1956, and has been in clinical use for
more than 30 years. Unfortunately, adverse side effects are
common [27]. Transient azotemia may occur in as many as 80%
of patients receiving the drug. Other well-recognized adverse
effects include febrile reactions and shaking chills during the
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infusion, nephrotoxicity, thrombophlebitis, electrolyte disorders, and anemia. Despite these reactions, amphotericin B remains the drug of choice for severe fungal infections [72].
The pharmacokinetics of amphotericin B in the pregnant
human have not been studied. To our knowledge, there have
been only six reports of measurement of amphotericin B concentrations in cord blood [52, 53, 62, 66, 68, 73]. In the three
reports in which simultaneous concentrations of maternal and
cord blood were reported, the amphotericin B concentrations
in these samples were 2.6 and 2.6 mg/mL, 1.9 and 1.3 mg/mL,
and 0.32 and 0.12 mg/mL, respectively [52, 53, 66]. Low levels
of the drug have also been detected in amniotic fluid [52,
66]. Although there is a wide disparity in these results, they
nonetheless confirm that amphotericin B crosses the placenta
to enter the fetal circulation and milieu.
In table 4 are listed 26 cases in which amphotericin B was
used in pregnancy, including 6 first-trimester exposures, 6 second-trimester exposures, and 14 third-trimester exposures.
Eleven patients received at least 900 mg during pregnancy; of
these, six received at least 1,500 mg. Azotemia was the most
common maternal adverse reaction, although anemia, hypokalemia, acute nephrotoxicity, fever, chills, headache, nausea, and
vomiting were also reported.
Possible fetal toxicity was manifested as the following in one
case each: transient acidosis with azotemia, anemia, transient
maculopapular rash, and respiratory failure requiring mechanical ventilation. None of these toxicities were related to elevated
amphotericin B serum concentrations. Closer examination of
the cases in which the mother received ú900 mg of amphotericin B during pregnancy reveals that seven of 11 babies showed
no adverse effects. Of the 25 cases listed, a single congenital
malformation was evident (microcephaly with a pilonidal
dimple).
A single case report indicates successful treatment of an
intraamniotic infection secondary to C. albicans with transcervical amnioinfusion of amphotericin B in a pregnant patient
who subsequently had a normal spontaneous vaginal delivery.
The infant was admitted to the neonatal intensive care unit for
mild respiratory distress. All cultures were negative for
C. albicans, and the neonate suffered no other sequelae [70].
To our knowledge, there have been no reports of animal teratogenesis attributed to amphotericin B. The manufacturer of this
agent has assigned it to risk category B [74].
Three lipid formulations of amphotericin B have recently
been marketed in the United States. Amphotericin B lipid complex (Abelcet; The Liposome Co., Princeton, NJ) was the first
to become available and is indicated for invasive fungal infections that are refractory to (or are in patients intolerant of)
conventional amphotericin B formulations. In animal studies,
doses up to 0.64 times the human dose have shown no detrimental effects on the fetus [75].
The second lipid formulation to be marketed was amphotericin B cholesteryl sulfate complex (Amphotec; Sequus Pharma-
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ceuticals, Menlo Park, CA). This agent is indicated for treatment of aspergillosis that is refractory to or for patients
intolerant of conventional amphotericin B. In animal studies
with this agent, use of up to 1.1 times the recommended human
dose has shown no detrimental effect on the fetus [76].
The most recent formulation to be marketed is amphotericin
B liposome (AmBisome; Nextar Pharmaceuticals, San Dimas,
CA), which is indicated for (1) empirical therapy in febrile,
neutropenic patients; (2) treatment of infections due to Aspergillus species, Candida species, or Cryptococcus species that
are refractory to or are in patients intolerant of conventional
amphotericin B; and (3) treatment of visceral leishmaniasis.
Rabbits receiving 0.5 – 2 times the recommended human dose
had a higher rate of spontaneous abortions than did a control
group [77].
There has been one report of the use of amphotericin B
liposome for treatment of Mediterranean visceral leishmaniasis
in a pregnant patient during the second trimester. This patient
was treated with a total dose of 18 mg/kg and subsequently
had a normal, uncomplicated vaginal delivery [68]. To date
there have been no reports of either of the other two products
having been used in pregnant women. The manufacturers have
assigned these amphotericin B formulations to risk category B
[75 – 77].
Azoles
The azole class of systemic antifungals includes the imidazoles and the more recently introduced triazoles. These drugs
have offered a less toxic alternative to amphotericin B for
the treatment of many of the fungi that produce deep-seated
infection. The azoles are active against a wide array of fungal
pathogens, including C. albicans and most of the agents of
systemic mycoses, including Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and to some degree
Aspergillis fumigatus. As mentioned previously, several azoles
are available in topical form. Available for systemic use are the
imidazoles (miconazole [intravenous] and ketoconazole [oral])
and the triazoles (fluconazole [intravenous and oral] and itraconazole [oral]).
Miconazole nitrate has limited use as an intravenous medication, and to our knowledge, no cases in which this agent was
used intravenously in human pregnancy have been reported.
Animal studies have demonstrated no teratogenicity at high
doses but have shown embryotoxicity and prolongation of gestation [20]. The intravenous form of miconazole is poorly tolerated by patients, and adverse side effects occur frequently [78].
Therefore, its use in the treatment of systemic fungal infections
is of only historical significance [79]. Most authorities simply
state that the effects of the intravenous form in pregnancy are
unknown [3, 4]. The manufacturer assigns the drug to risk
category C [80].
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Antifungal Therapy During Pregnancy
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Table 4. Data concerning the use of amphotericin B in pregnancy.
No. of
trimester in
which
therapy was
initiated
Disease [reference]
Total dose or
dosage given
during pregnancy
Toxic effect(s) of drug
on mother
Possible toxic
effect(s) on fetus
C-section, maternal death
Spontaneous vaginal delivery
of twins (1,420/1,530 g)
Spontaneous vaginal delivery
(2,720 g)
...
...
...
Small for age, anemia
...
Hypokalemia, anemia
Reversible azotemia,
anemia,
hypokalemia
Azotemia, anemia
...
Anemia
Transient acidosis,
increased SCr,
microcephaly,
pilonidal dimple
None
None
Outcome (birth weight)
Histoplasmosis [50]
Blastomycosis [51]
3
2
Unknown
900 mg
Blastomycosis [51]
3
975 mg
Blastomycosis [52]
Blastomycosis [53]
3
3
501 mg
1,536 mg
Induced labor (3,600 g)
Spontaneous vaginal delivery
(3,632 g)
Blastomycosis [54]
Blastomycosis [55]
Cryptococcosis [56]
3
3
2
1,000 mg
õ165 mg
12 d iv, 1 dose ith
Vaginal delivery (2,070 g)
C-section (‘‘healthy’’ infant)
. . . (2,073 g)
Cryptococcosis [57]
Cryptococcosis [58]
2
1
1 w iv
2,507 mg
Cryptococcosis [58]
3
2,242 mg
Maternal, fetal death
Spontaneous labor, term
(2,891 g)
C-section (2,806 g)
Cryptococcosis [59]
Cryptococcosis [60]
2
3
...
At least 1,500 mg
Cryptococcosis [61]
3
At least 650 mg iv,
12 mg ith
õ200 mg
Ç750 mg
1,900 mg
õ500 mg
...
2,000 mg
Cryptococcosis [62]
Coccidioidomycosis
Coccidioidomycosis
Coccidioidomycosis
Coccidioidomycosis
Coccidioidomycosis
[63]
[63]
[64]
[64]
[65]
1
3
2
3
1
1
Coccidioidomycosis [66]
3
Coccidioidomycosis [67]
1
1 (subsequent
pregnancy)
2
Mediterranean visceral
leishmaniasis [68]
Candida glabrata
candidemia [69]
Intraamniotic infection
with Candida
albicans [70]
Cryptococcal meningitis
[71]
3
3
3
0.6 mg/kg every
other day for
9w
20 mg ith
17.8 mg ith
...
Anemia, hypokalemia
...
Spontaneous vaginal delivery
(2,727 g)
Spontaneous vaginal delivery
(2,869 g)
Elective termination
‘‘Normal delivery’’ of twins
‘‘Normal delivery’’
Induced labor (2,031 g)
. . . (3,250 g)
‘‘Normal’’ term delivery
(3,175 g)
Vacuum extraction (3,189 g)
Anemia (concurrent
5-FC treatment)
...
Anemia, chills,
nausea, vomiting
Azotemia, fever,
headache, vomiting
...
Azotemia
Azotemia
Azotemia
None
Azotemia,
hypokalemia
...
...
Respiratory failure
(ventilation)
...
None
None
None
None
Transient
maculopapular rash
...
None
None
None
None
None
None
‘‘Normal’’ delivery (3,430 g)
C-section (3,884 g)
...
None
None
Liposomal, 18
mg/kg (total)
1,020 mg
‘‘Normal’’ delivery
...
None
54 mg
(transcervical
amnioinfusion)
50 mg/d for 3 w
Normal spontaneous vaginal
delivery (1,030 g)
Normal spontaneous vaginal
delivery
Hypokalemia,
hypomagnesemia,
increased SCr
...
Induced labor (2,900 g)
...
NOTE. C-section Å cesarean section; 5-FC Å flucytosine; ith Å intrathecally; SCr Å serum creatinine level; . . . Å not stated.
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Increased SCr
Mild respiratory
distress
...
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The use of systemic ketoconazole in pregnancy is even more
problematic. This agent has proven both teratogenic and embryotoxic at high doses (80 mg/kg) in animals. In addition,
doses of 1.25 times the normal human dose caused prolongation
of labor in third-trimester rats [81]. Whether these effects in
animals are related to maternal toxicity or to direct fetal toxicity
is uncertain. The drug does cross the placenta, although to what
degree is unknown [82].
Of major concern is ketoconazole’s well-described inhibition
of both gonadal and adrenal steroid synthesis in humans [83],
resulting in decreased plasma testosterone and adrenal responses to adrenocorticotrophic hormone. Theoretically, this
endocrine effect might alter the differentiation of sexual organs
in the human fetus, which is known to be influenced by local
concentrations of sex hormones.
An instance of late-trimester exposure in a patient with Cushing’s syndrome is the only case in which the use of ketoconazole in human pregnancy has been documented. Although the
infant (delivered by elective cesarean section) suffered no adverse effects, the authors of this case report emphasize that
they knew the sex of the female child prior to institution of
the drug treatment late in pregnancy [84]. Although the manufacturer has assigned the drug to risk category C, most authorities advise that this drug not be used in pregnancy [85, 86].
The triazoles are a newer class of antifungal agents that have
proven useful in the treatment of systemic fungal infections.
The first triazole to become available was fluconazole, available
in both oral and intravenous formulations. Fluconazole has
been shown to be teratogenic and embryotoxic at high doses
in rats and is assigned to risk category C by its manufacturer
[87]. Congenital anomalies have been reported in four infants
whose mothers used fluconazole during pregnancy [88 – 90].
Lee and colleagues reported a case of congenital malformation resembling the genetic disorder Antley-Bixler syndrome
in an infant born to a 22-year-old woman receiving fluconazole
(400 mg orally once daily) for treatment of disseminated coccidioidomycosis throughout her pregnancy. She experienced
premature rupture of the membranes at 27 weeks’ gestation
and subsequently underwent cesarean section.
She delivered a premature female infant with grossly dysmorphic features including radiographic findings of craniosynostosis, humoral-radial fusion, bowed tibia and femur, and
bilateral femoral fractures. Other findings at autopsy included
hypoplasia of nasal bones, cleft palate, contractures of both
upper and lower extremities, an incompletely formed right
thumb, medial deviation of both feet, shortened toes, cranioschisis of the frontal bones, and craniostenosis of the sagittal
suture. The infant died shortly after birth [88].
Pursley and colleagues reported two similar cases; the first
infant was born to a 25-year-old woman receiving fluconazole
(800 mg daily) for treatment of C. immitis meningitis [89]. She
became pregnant and at 7 weeks’ gestation was advised to
discontinue therapy. The patient chose to continue therapy
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throughout her pregnancy and underwent cesarean delivery at
38 weeks of gestation. She delivered a boy with malformations
similar to those reported by Lee et al. [88].
The second case presented in the report by Pursley and
colleagues [89] involved a sibling of the infant described by
Lee et al. [88]. The mother of these two infants had continued
to receive fluconazole (400 mg daily) for treatment of disseminated coccidioidomycosis. In a pregnancy subsequent to the one
described above, the mother was documented to be noncompliant with fluconazole therapy on the basis of serum drug-concentration measurements, and she delivered a healthy boy. During
her fourth pregnancy, the patient was compliant with fluconazole therapy, again documented by serum drug-concentration
measurement, and continued to receive fluconazole through the
fourth month of gestation. She subsequently delivered a girl
with congenital abnormalities similar to those of the abovementioned infant [88].
The fourth case involves a mother, also treated for coccidioidal meningitis, who received 400 mg/d for the first 5 weeks
of gestation, after which time the dosage was changed to
800 mg/d. Fluconazole was withdrawn upon discovery of the
pregnancy, and the patient began receiving amphotericin B
at 9 weeks’ gestation. Therapy with amphotericin B was discontinued and that with fluconazole was restarted at 22
weeks, at a dosage of 1,200 mg/d. Spontaneous rupture of
the membranes occurred at 31 weeks, and a boy was delivered
by cesarean section with congenital anomalies similar to
those noted above.
These observations, as well as animal studies conducted by
Tiboni, suggest that the teratogenic effects of fluconazole may
be dose-dependent [91]. Inman et al. conducted a prescriptionevent-monitoring study evaluating the safety of fluconazole in
the treatment of vaginal candidiasis. There was no unusual
pattern of fetal abnormalities among 289 women who received
single or multiple daily doses of fluconazole (150 mg) at some
time before or during pregnancy [92].
More recently, Mastroiacovo and colleagues performed a
prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. They compared 226 women
exposed to this agent (at dosages £150 mg daily) to 452
women exposed to nonteratogenic agents. They found no difference in prevalences of miscarriages, congenital anomalies,
or low birth weight [93]. It should be noted that, since the
study of Inman et al. [91], every year thousands of pregnant
women have inadvertently received fluconazole at daily doses
of £150 mg without untoward effects (Pfizer, Groton, CT;
data on file). This dosage is much lower than the 400 – 800mg daily doses noted in the above case reports.
Less information is available concerning itraconazole. To
our knowledge, there have been no reports of its use in human
pregnancy. Itraconazole has been found to be embryotoxic and
teratogenic in laboratory animals. Teratogenic effects observed
included major skeletal defects, encephaloceles, and macro-
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Antifungal Therapy During Pregnancy
glossia. The manufacturer has assigned itraconazole to risk
category C and recommends use of effective contraception for
2 months following treatment [89, 94].
1157
independent epidemiological investigations [3]. These concerns, and the fact that this drug is not prescribed for lifethreatening fungal infections, indicate that griseofulvin is best
avoided during pregnancy [4, 86].
Flucytosine
Flucytosine (5-fluorocytosine, or 5-FC) is a fluorine analog
of cytosine. Its usefulness as an antifungal agent is limited to
yeast infections (due to Candida, Cryptococcus, and Torulopsis
species) and is hindered by the prompt development of resistance [78]. Side effects of this oral medication are common
and can be severe, including gastrointestinal symptoms, hepatic
dysfunction, and bone marrow suppression (particularly with
blood concentrations ú125 mg/mL).
Flucytosine is teratogenic in rats at doses less than the human
dose on a milligram-per-kilogram basis [95]. Its teratogenic
properties may be related to the fact that a portion of the
drug is metabolized to 5-fluorouracil, an antineoplastic agent
suspected of causing congenital defects in humans [3]. The
drug crosses the human placenta, as evidenced by a case in
which drug levels in amniotic fluid and mixed cord blood were
measured in a woman with cryptococcal meningitis at 21
weeks’ gestation. The mother received the drug for only 1
week prior to elective termination of the pregnancy. A concentration of 168 mg/mL was detected in amniotic fluid 4 hours
after a 2-g oral dosing, and mixed cord blood showed a concentration of 68 mg/mL after the patient had received 4 g that day
[62].
In addition to the above case, three other cases in which
flucytosine was used in human pregnancy have been reported
[58, 96, 97]. All were late exposures, with two in the second
trimester and one in the third. Maternal bone marrow suppression occurred in one case. No adverse fetal effects were noted.
Although the drug is assigned to risk category C by its manufacturer, other authorities believe it is contraindicated in pregnancy [73, 86].
Griseofulvin
Griseofulvin is an organically derived antifungal agent useful
as an oral preparation in the treatment of ringworm. The drug
is usually well tolerated, although reported side effects include
headache and (rarely) other neurological symptoms, gastrointestinal distress, and severe hepatotoxic reactions (the latter in
patients with acute intermittent porphyria).
The drug is embryotoxic and teratogenic in animals exposed
to high doses [98]. In studies by Rubin and Dvormik, griseofulvin was reported to have crossed the human placenta [99].
When given to 12 women prior to cesarean section or induction
of labor, drug levels in cord blood ranged from 48% to 100%
of simultaneous maternal blood levels. The FDA has also reported an association between first-trimester drug exposure and
conjoined twins in two cases, a finding unsupported by two
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Terbinafine
The latest systemic antifungal agent to be marketed is terbinafine, an oral squalene epoxidase inhibitor that is indicated
for onychomycosis of the toenail and fingernail due to dermatophytes. Animal studies have revealed no evidence of harm to
the fetus. To our knowledge, there have been no reports of the
use of terbinafine in pregnancy. The manufacturer has assigned
this product to risk category B, but the lack of human data
makes this designation somewhat arbitrary [100].
Potassium Iodide
Oral potassium iodide remains the treatment of choice for
cutaneous infection caused by Sporothrix schenckii, although
the triazole drug itraconazole may be useful in this condition
as well [101]. Iodides are generally considered contraindicated
in pregnancy because of their association with congenital goiter, which can be a fatal condition for the newborn. Among
49 cases reviewed in 1983, 14 deaths occurred secondary to
tracheal compression [102]. Although short courses used in
preoperative management of hyperthyroidism in pregnancy are
reported to be safe [3], the American Academy of Pediatrics
and other authorities advise against the use of iodide-containing
drugs during pregnancy [4, 103].
A single case in which cutaneous sporotrichosis in pregnancy
was treated with potassium iodide has been reported [104].
The patient was treated from conception until 2 months prior
to delivery, at which time therapy was stopped because of
concern about possible goiter formation in the infant. The patient delivered a healthy infant with no evidence of goiter or
thyroid dysfunction. Other cases of cutaneous sporotrichosis
in pregnancy have been treated successfully with the local
application of heat [105, 106].
Conclusion
Most of the antifungal medications in current use have become available in the past 30 years; nevertheless, experience
with topical and systemic agents in human pregnancy is limited.
When prescribing medications to pregnant women, it is good
practice to exercise added caution with recently released medications. Often a number of years and thousands of exposures
are required for a particular effect to become evident.
Animal studies, although suggestive, cannot be entirely extrapolated to human pregnancy. Such was the case with thalidomide, a powerful human teratogen that did not produce malformation in animals. Some effects may be long-delayed in their
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King et al.
presentation, as exemplified by diethylstilbestrol, which produces an increased incidence of vaginal cancers in mature offspring of exposed mothers. Caution is prudent, and the best
policy is to avoid drug exposure if possible.
When local treatment is necessary, short courses of topical
antifungal agents are likely safe in pregnancy. We prefer the
imidazole compounds for cutaneous use because of their excellent antifungal activity and because there is only minimal systemic absorption. Nystatin and the imidazoles are safe for vaginal use throughout pregnancy. Nystatin has accrued a
considerable safety record in human pregnancy, is not an animal teratogen, and is minimally absorbed from vaginal mucosa.
Although imidazoles are likely safe, especially in the latter
two-thirds of pregnancy, their systemic absorption is higher
when applied vaginally than when applied to skin.
Amphotericin B is the drug of choice for systemic fungal
infections that threaten the life of the mother in pregnancy.
This agent is effective for the endemic mycoses as well as
serious yeast infections, and it has been used in human pregnancy with no consistent adverse fetal effects. Maternal toxic
effects are to be expected, and any use of this drug in the
pregnant female should be closely monitored.
At present, use of the other systemic agents cannot be recommended in pregnancy, although inadvertent use of fluconazole
in pregnancy at doses of £150 mg has not appeared to be
harmful. In individual cases in which amphotericin B cannot
be used or an additional drug is indicated, however, the clinician must weigh the risk to the fetus and the benefit to the
mother in choosing appropriate therapy. Time may demonstrate
that many of the newer drugs are indeed safe for use in pregnancy, but the converse may also prove true. Prudent use of
these agents in the pregnant patient is therefore warranted.
Acknowledgment
The authors thank Dr. Jack D. Sobel for his meticulous review
and invaluable comments during preparation of the manuscript.
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