Clin Infect Dis.-1998-King-1151-60.pdf

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1151

Antifungal Therapy During Pregnancy

Coleman T. King, P. David Rogers, John D. Cleary, and From the Section of General Internal Medicine, Department of Medicine, School of Medicine, University of Georgia, Augusta, Georgia;Stanley W. Chapman

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 deli- A number of publications are available to aid clinicians in

choosing the safest drug therapy for a pregnant patient [3cate balance between the mothers need for treatment and the

potential risk of damage to the fetus, including congenital mal- 5]. In 1980, the U.S. Food and Drug Administration (FDA)

published definitions for pregnancy risk categories [6]. Asformations, adverse effects, and the health of the pregnancy

itself. Although the dictum No drug should be considered shown in table 1, categories A through D and X are assigned

in accordance with a products estimated potential harm to aabsolutely safe during pregnancy cannot be questioned, most

practitioners find this impractical. There are instances in which fetus. These designations provide a grading scale by which to

rate a products relative risk of use in pregnancy. They arepregnant women require medications. Fortunately, scientific

data and reports on clinical experience are available to provide derived from pooled data from various pharmacological inves-

tigations, animal studies, and clinical experience. Although notguidance when drug therapy during pregnancy is necessary.

The use of antifungal medications in pregnancy is addressed absolute, these categories serve as general guidelines and are

listed in most major texts and in individual-product mono-in this report. References were selected by a MEDLINE search

of the English-language literature from 1966 to the present, graphs. It should be noted that manufacturers are not requiredto provide pregnancy risk categories for drugs marketed beforeincluding reference citations and relevant articles.

Pregnant women are susceptible to the same fungal infec- December 1983.

tions as are nonpregnant women, and in some cases their risks

are increased. Candidal vaginitis, for example, is common inTopical Therapy

nonpregnant patients, but it is more common, more frequently

refractory to therapy, and more likely to relapse in pregnant Fungal infections of the skin, hair, and nails are a common

clinical problem. The majority of these infections are causedpatients [1]. Pregnancy is also associated with more systemic

and serious fungal infections. Coccidioidomycosis is believed by dermatophytes, although yeasts such as Malassezia furfur

andCandida albicansare also frequently implicated [7]. Theseto disseminate more frequently in pregnant females [2]. Other

systemic mycoses occasionally occur in pregnancy and present infections are usually responsive to topical medications when

a small area of the skin is involved. Extensive cutaneous diseasetherapeutic dilemmas in which two lives are involved.

and/or hair or nail involvement, however, often requires a

course of oral agents such as ketoconazole, fluconazole, itraco-

nazole, griseofulvin, or terbinafine for resolution. Unfortu-

nately, therapy with both topical and systemic antifungal agentsReceived 15 January 1998; revised 16 June 1998.

is associated with high relapse rates.Reprints or correspondence: Stanley W. Chapman, Division of InfectiousDiseases, Department of Medicine, School of Medicine, Jackson, Mississippi Numerous topical antifungals are available in both prescrip-39216-4505.

tion and nonprescription preparations. Chemical compoundsClinical Infectious Diseases 1998;27:115160 such as ammonium derivatives, chlorinated or iodinated com- 1998 by the Infectious Diseases Society of America. All rights reserved.10584838/98/27050007$03.00 pounds, phenols, and dyes have been used over the years, but

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1152 King et al. CID 1998; 27 (November)

Table 1. Classification of prescription drugs by the U.S. Food and fetus have not been fully elucidated and the bases that serveDrug Administration, according to risk in pregnancy. as vehicles for these agents contain a variety of chemical com-

pounds.Pregnancy risk

category Description

Vaginal TherapyA Controlled studies of women failed to demonstrate a riskto the fetus in the first trimester, and the possibility of

The available intravaginal antifungal preparations are listedfetal harm appears remote.in table 3. Imidazoles and nystatin are the mainstays of topicalB Either animal studies do not indicate a risk to the fetus

and there have been no controlled studies of pregnant therapy for candidal vaginitis [19 26]. These agents have beenwomen, or animal studies have indicated fetal risk but widely used in pregnancy, and both retrospective and prospec-controlled studies of pregnant women failed to tive comparative trials suggest that they are reasonably safe.demonstrate a risk.

Most manufacturers, however, caution against their use duringC Either animal studies indicate a fetal risk and there have

the first trimester. With the exception of terconazole, all of thebeen no controlled studies of women, or there are noavailable reports of studies of women or animals. topical azole preparations are now available over the counter.

D There is positive evidence of fetal risk, but there may be Nystatin, a polyene antifungal discovered in 1949, representscertain situations where the benefit may outweigh the one of the first antifungal agents isolated [27]. The drug is notrisk (e.g., life-threatening or serious diseases for

absorbed after ingestion and is toxic when given intravenously.which other drugs are ineffective or carry a greater

Therefore, nystatin is used only topically. Systemic absorptionrisk).X There is definite fetal r isk, according to studies of of nystatin after topical or mucosal application is negligible

animals or humans or on the basis of human [19]. To our knowledge, there have been no reports of animalexperience, and the risk clearly outweighs any benefit or human teratogenesis with this agent.in pregnant women.

Extensive data for intravaginal application of nystatin during

the first trimester of human pregnancy are available. Rosa etNOTE. This table is adapted from the Federal Register [6].al. found no increased risk of congenital malformations in 842

first-trimester exposures [28]. The National Institutes of Healthlittle is known regarding their safety in pregnancy. Some of Collaborative Perinatal Project reported a slight increased riskthe commonly used topical antifungal agents are shown in of congenital malformations in a series of 142 women withtable 2. The imidazoles (clotrimazole, econazole, miconazole, first-trimester exposures, but this was attributed to concurrentoxiconazole, ketoconazole, and sulconazole) are active against

ringworm, tinea versicolor, and cutaneous candidal infections

[8]. Although some imidazoles have been shown to be terato-Table 2. Topical antifungal agents.

genic or embryotoxic at high oral doses in the rat [9 13],

they are generally considered safe for topical use in human Agent Risk categorypregnancy [3, 4]. The topical dose is a small fraction of the

Nonprescriptiondose used in these animal studies, and systemic absorption ofClioquinol NA

imidazole compounds is minimal when they are applied toClotrimazole B

human skin. Miconazole CThe polyenes (amphotericin B and nystatin) likewise are Naftifine B

Nystatin Bminimally absorbed from skin, but because of a narrower spec-Tolnaftate NAtrum of activity, they are of limited benefit in the treatment ofUndecylenic acid NA

ringworm [14, 15]. Terbinafine cream is effective for treatmentPrescription

of tinea pedis, tinea corporis, and tinea cruris. However, there Amphotericin B Bare no data regarding systemic absorption of topical terbinafine Butoconazole C

Ciclopirox Bin humans, and there have been no adequate, well-controlledEconazole Cstudies of the use of this agent by pregnant women. AlthoughHaloprogin Bother agents such as naftifine, tolnaftate, ciclopirox, and halo-Ketoconazole C

progin provide excellent activity against dermatophytes, they Oxiconazole Bhave higher systemic absorption after local application than do Sulconazole C

Terbinafine Bthe imidazoles, and data regarding their use in human preg-Terconazole Cnancy are lacking [1618]. None of these topical preparationsTioconazole C

have been implicated as a cause of fetal or maternal harm inTriacetin NA

human pregnancy. Indiscriminate use in pregnancy should be

NOTE. NA manufacturer has not assigned agent to a risk category.avoided, however, as the effects of these drugs on the human

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1153CID 1998; 27 (November) Antifungal Therapy During Pregnancy

Table 3. Topical vaginal antifungal agents.

Risk Systemic Embryotoxic

Drug category* absorption* in animals* Human trials

Nystatin A Negligible No data Safe in all trimesters

Miconazole C 1.4% Yes Possibly increased risk of spontaneous

abortion

Clotrimazole B Up to 3% 10% Yes Safe in second and third trimesters

Butoconazole C 5.5% Yes Safe in second and third trimesters

Terconazole C 5% 16% Yes Safe in second and third trimesters

Tioconazole C Negligible Yes No data

NOTE. None of the oral or systemic azoles have received approval by the U.S. Food and Drug Administrationfor use in any trimester of pregnancy.

* Product monograph information from [1924], unless otherwise specified.

tetracycline therapy [29]. The Group Health Cooperative of Trials with limited numbers of patients have shown no ad-

verse fetal or maternal effects linked to the use of butoconazolePuget Sound study found no increased risk of fetal malforma-

tions or other adverse effects with 225 first-trimester exposures in the second and third trimesters of pregnancy [22, 47]. Terco-

nazole is absorbed vaginally to some degree in humans andfrom 1977 to 1979 [30] and with 176 exposures from 1980 to

1982 [31]. may cross the amniotic membrane. One study reported a 2.9%incidence of birth defects in 1,167 first-trimester exposures [3].In addition, numerous trials have compared nystatin with

other agents for use in pregnant women [3241]. The largest Insufficient published data are available regarding the use of

tioconazole and econazole in human pregnancy [48].such study, that of McNellis et al., included 53 first-trimester

exposures and 191 exposures in later trimesters and showed In summary, the only data against use of the imidazoles in

pregnancy are those of Rosa et al. [28] regarding miconazoleno increase over the expected number of fetal or neonatal

deaths [42]. during the first trimester. The other imidazoles have been less

well studied, and few or no data are available. Although theImidazoles are the other commonly used topical agents for

treatment of yeast vaginitis. In the studies comparing imida- Centers for Disease Control and Prevention previously recom-

mended only nystatin for therapy during the first trimester,zoles to nystatin, imidazoles have uniformly superior cure rates

and lower relapse rates [32, 33, 35, 37, 38]. In a study of their most recent recommendations support the use of azoles

specifically, butoconazole, clotrimazole, miconazole, and ter-volunteers, 1.4% of the topical vaginal dose of miconazole was

recovered in the urine and feces after 96 hours [25]. Although conazole for vaginal therapy in all trimesters [49].

animal studies utilizing high doses of this drug have demon-strated both embryotoxicity and prolongation of gestation [20],

Systemic Therapymiconazole has been used frequently and, for the most part,

safely in human pregnancies. Systemic antifungal agents have traditionally been regarded

as toxic medications, and their use in pregnancy has been lim-Weisberg reviewed studies in which a total of 471 patients

had used miconazole during pregnancy without adverse mater- ited to life-threatening fungal infections. Thus, very little infor-

mation is available on the use of these drugs in pregnancy. Innal or fetal effects [43]. McNellis et al. demonstrated the overall

safety of this product in 291 pregnant women, 43 of whom contrast to the vaginal antifungals, no large-scale trials have

been performed, and any existing data on the use of thesewere 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 agents in human pregnancy are from isolated case reports.

(95% CI, 0.91.2); however, this was not statistically signifi-

cant and this study has been the subject of some debate [28].Amphotericin B

Fewer data are available concerning the use of clotrimazole

in pregnancy. Vaginal absorption is estimated at 3% 10% of The systemic antifungal drug with which there has been the

most experience in human pregnancy is amphotericin B [50the topically applied dose [26]. Animal studies have shown

decreases in litter size and number of viable young with high- 71]. This polyene antifungal was first demonstrated to have

antifungal properties in 1956, and has been in clinical use fordose exposure [21] but no adverse effects of vaginal therapy

during pregnancy. Rosa et al. showed no increased risk of more than 30 years. Unfortunately, adverse side effects are

common [27]. Transient azotemia may occur in as many as 80%adverse fetal effects in 1,012 first-trimester exposures [28].

Other studies in pregnancy with considerably fewer patients of patients receiving the drug. Other well-recognized adverse

effects include febrile reactions and shaking chills during thehave supported this finding [32, 33, 3739, 4446].

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infusion, nephrotoxicity, thrombophlebitis, electrolyte disor- ceuticals, Menlo Park, CA). This agent is indicated for treat-

ment of aspergillosis that is refractory to or for patientsders, and anemia. Despite these reactions, amphotericin B re-

mains the drug of choice for severe fungal infections [72]. intolerant of conventional amphotericin B. In animal studies

with this agent, use of up to 1.1 times the recommended humanThe pharmacokinetics of amphotericin B in the pregnant

human have not been studied. To our knowledge, there have dose has shown no detrimental effect on the fetus [76].

The most recent formulation to be marketed is amphotericinbeen only six reports of measurement of amphotericin B con-

centrations in cord blood [52, 53, 62, 66, 68, 73]. In the three B liposome (AmBisome; Nextar Pharmaceuticals, San Dimas,CA), which is indicated for (1) empirical therapy in febrile,reports in which simultaneous concentrations of maternal and

cord blood were reported, the amphotericin B concentrations neutropenic patients; (2) treatment of infections due toAsper-

gillusspecies, Candida species, orCryptococcus species thatin 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 are refractory to or are in patients intolerant of conventional

amphotericin B; and (3) treatment of visceral leishmaniasis.of the drug have also been detected in amniotic fluid [52,

66]. Although there is a wide disparity in these results, they Rabbits receiving 0.52 times the recommended human dose

had a higher rate of spontaneous abortions than did a controlnonetheless confirm that amphotericin B crosses the placenta

to enter the fetal circulation and milieu. group [77].

There has been one report of the use of amphotericin BIn table 4 are listed 26 cases in which amphotericin B was

used in pregnancy, including 6 first-trimester exposures, 6 sec- liposome for treatment of Mediterranean visceral leishmaniasis

in a pregnant patient during the second trimester. This patientond-trimester exposures, and 14 third-trimester exposures.

Eleven patients received at least 900 mg during pregnancy; of was treated with a total dose of 18 mg/kg and subsequently

had a normal, uncomplicated vaginal delivery [68]. To datethese, six received at least 1,500 mg. Azotemia was the mostcommon maternal adverse reaction, although anemia, hypoka- there have been no reports of either of the other two products

having been used in pregnant women. The manufacturers havelemia, acute nephrotoxicity, fever, chills, headache, nausea, and

vomiting were also reported. assigned these amphotericin B formulations to risk category B

[7577].Possible fetal toxicity was manifested as the following in one

case each: transient acidosis with azotemia, anemia, transient

maculopapular rash, and respiratory failure requiring mechani-

cal ventilation. None of these toxicities were related to elevated Azolesamphotericin B serum concentrations. Closer examination of

the cases in which the mother received900 mg of amphoteri- The azole class of systemic antifungals includes the imidaz-

oles and the more recently introduced triazoles. These drugscin B during pregnancy reveals that seven of 11 babies showed

no adverse effects. Of the 25 cases listed, a single congenital have offered a less toxic alternative to amphotericin B for

the treatment of many of the fungi that produce deep-seatedmalformation was evident (microcephaly with a pilonidal

dimple). infection. The azoles are active against a wide array of fungalpathogens, including C. albicans and most of the agents ofA single case report indicates successful treatment of an

intraamniotic infection secondary to C. albicanswith transcer- systemic mycoses, includingHistoplasma capsulatum, Blasto-

myces dermatitidis, Coccidioides immitis, and to some degreevical amnioinfusion of amphotericin B in a pregnant patient

who subsequently had a normal spontaneous vaginal delivery. Aspergillis fumigatus.As mentioned previously, several azoles

are available in topical form. Available for systemic use are theThe infant was admitted to the neonatal intensive care unit for

mild respiratory distress. All cultures were negative for imidazoles (miconazole [intravenous] and ketoconazole [oral])

and the triazoles (fluconazole [intravenous and oral] and itraco-C. albicans, and the neonate suffered no other sequelae [70].

To our knowledge, there have been no reports of animal terato- nazole [oral]).

Miconazole nitrate has limited use as an intravenous medica-genesis attributed to amphotericin B. The manufacturer of this

agent has assigned it to risk category B [74]. tion, and to our knowledge, no cases in which this agent was

used intravenously in human pregnancy have been reported.Three lipid formulations of amphotericin B have recently

been marketed in the United States. Amphotericin B lipid com- Animal studies have demonstrated no teratogenicity at high

doses but have shown embryotoxicity and prolongation of ges-plex (Abelcet; The Liposome Co., Princeton, NJ) was the first

to become available and is indicated for invasive fungal infec- tation [20]. The intravenous form of miconazole is poorly toler-

ated by patients, and adverse side effects occur frequently [78].tions that are refractory to (or are in patients intolerant of)

conventional amphotericin B formulations. In animal studies, Therefore, its use in the treatment of systemic fungal infections

is of only historical significance [79]. Most authorities simplydoses up to 0.64 times the human dose have shown no detri-

mental effects on the fetus [75]. state that the effects of the intravenous form in pregnancy are

unknown [3, 4]. The manufacturer assigns the drug to riskThe second lipid formulation to be marketed was amphoteri-

cin B cholesteryl sulfate complex (Amphotec; Sequus Pharma- category C [80].

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Table 4. Data concerning the use of amphotericin B in pregnancy.

No. of

trimester in

which Total dose or

therapy was dosage given Toxic effect(s) of drug Possible toxic

Disease [reference] initiated during pregnancy Outcome (birth weight) on mother effect(s) on fetus

Histoplasmosis [50] 3 Unknown C-section, maternal death . . . . . .

Blastomycosis [51] 2 900 mg Spontaneous vaginal delivery . . . Small for age, anemia

of twins (1,420/1,530 g)

Blastomycosis [51] 3 975 mg Spontaneous vaginal delivery . . . Transient acidosis,

(2,720 g) increased SCr,

microcephaly,

pilonidal dimple

Blastomycosis [52] 3 501 mg Induced labor (3,600 g) Hypokalemia, anemia None

Blastomycosis [53] 3 1,536 mg Spontaneous vaginal delivery Reversible azotemia, None

(3,632 g) anemia,

hypokalemia

Blastomycosis [54] 3 1,000 mg Vaginal delivery (2,070 g) Azotemia, anemia None

Blastomycosis [55] 3 165 mg C-section (healthy infant) . . . . . .

Cryptococcosis [56] 2 12 d iv, 1 dose ith . . . (2,073 g) Anemia Respiratory failure

(ventilation)

Cryptococcosis [57] 2 1 w iv Maternal, fetal death . . . . . .Cryptococcosis [58] 1 2,507 mg Spontaneous labor, term Anemia, hypokalemia None

(2,891 g)

Cryptococcosis [58] 3 2,242 mg C-section (2,806 g) Anemia (concurrent None

5-FC treatment)

Cryptococcosis [59] 2 . . . . . . . . . None

Cryptococcosis [60] 3 At least 1,500 mg Spontaneous vaginal delivery Anemia, chills, None

(2,727 g) nausea, vomiting

Cryptococcosis [61] 3 At least 650 mg iv, Spontaneous vaginal delivery Azotemia, fever, Transient

12 mg ith (2,869 g) headache, vomiting maculopapular rash

Cryptococcosis [62] 1 200 mg Elective termination . . . . . .

Coccidioidomycosis [63] 3 750 mg Normal delivery of twins Azotemia None

Coccidioidomycosis [63] 2 1,900 mg Normal delivery Azotemia None

Coccidioidomycosis [64] 3 500 mg Induced labor (2,031 g) Azotemia None

Coccidioidomycosis [64] 1 . . . . . . (3,250 g) None None

Coccidioidomycosis [65] 1 2,000 mg Normal term delivery Azotemia, None(3,175 g) hypokalemia

Coccidioidomycosis [66] 3 0.6 mg/kg every Vacuum extraction (3,189 g) . . . None

other day for

9 w

Coccidioidomycosis [67] 1 20 mg ith Normal delivery (3,430 g) . . . None

1 (subsequent 17.8 mg ith C-section (3,884 g) None

pregnancy)

Mediterranean visceral 2 Liposomal, 18 Normal delivery . . . None

leishmaniasis [68] mg/kg (total)

Candida glabrata 3 1,020 mg Normal spontaneous vaginal Hypokalemia, Increased SCr

candidemia [69] delivery hypomagnesemia,

increased SCr

Intraamniotic infection 3 54 mg Normal spontaneous vaginal . . . Mild respiratory

with Candida (transcervical delivery (1,030 g) distress

albicans [70] amnioinfusion)

Cryptococcal meningitis 3 50 mg/d for 3 w Induced labor (2,900 g) . . . . . .

[71]

NOTE. C-section cesarean section; 5-FC flucytosine; ith intrathecally; SCr serum creatinine level; . . . not stated.

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The use of systemic ketoconazole in pregnancy is even more throughout her pregnancy and underwent cesarean delivery at

38 weeks of gestation. She delivered a boy with malformationsproblematic. This agent has proven both teratogenic and em-

bryotoxic at high doses (80 mg/kg) in animals. In addition, similar to those reported by Lee et al. [88].

The second case presented in the report by Pursley anddoses of 1.25 times the normal human dose caused prolongation

of labor in third-trimester rats [81]. Whether these effects in colleagues [89] involved a sibling of the infant described by

Lee et al. [88]. The mother of these two infants had continuedanimals are related to maternal toxicity or to direct fetal toxicity

is uncertain. The drug does cross the placenta, although to what to receive fluconazole (400 mg daily) for treatment of dissemin-ated coccidioidomycosis. In a pregnancy subsequent to the onedegree is unknown [82].

Of major concern is ketoconazoles well-described inhibition described above, the mother was documented to be noncompli-

ant with fluconazole therapy on the basis of serum drug-concen-of both gonadal and adrenal steroid synthesis in humans [83],

resulting in decreased plasma testosterone and adrenal re- tration measurements, and she delivered a healthy boy. During

her fourth pregnancy, the patient was compliant with flucona-sponses to adrenocorticotrophic hormone. Theoretically, this

endocrine effect might alter the differentiation of sexual organs zole therapy, again documented by serum drug-concentration

measurement, and continued to receive fluconazole through thein the human fetus, which is known to be influenced by local

concentrations of sex hormones. fourth month of gestation. She subsequently delivered a girl

with congenital abnormalities similar to those of the above-An instance of late-trimester exposure in a patient with Cush-

ings syndrome is the only case in which the use of ketocona- mentioned infant [88].

The fourth case involves a mother, also treated for coccidi-zole in human pregnancy has been documented. Although the

infant (delivered by elective cesarean section) suffered no ad- oidal meningitis, who received 400 mg/d for the first 5 weeks

of gestation, after which time the dosage was changed toverse effects, the authors of this case report emphasize thatthey knew the sex of the female child prior to institution of 800 mg/d. Fluconazole was withdrawn upon discovery of the

pregnancy, and the patient began receiving amphotericin Bthe drug treatment late in pregnancy [84]. Although the manu-

facturer has assigned the drug to risk category C, most authori- at 9 weeks gestation. Therapy with amphotericin B was dis-

continued and that with fluconazole was restarted at 22ties advise that this drug not be used in pregnancy [85, 86].

The triazoles are a newer class of antifungal agents that have weeks, at a dosage of 1,200 mg/d. Spontaneous rupture of

the membranes occurred at 31 weeks, and a boy was deliveredproven useful in the treatment of systemic fungal infections.

The first triazole to become available was fluconazole, available by cesarean section with congenital anomalies similar to

those noted above.in both oral and intravenous formulations. Fluconazole has

been shown to be teratogenic and embryotoxic at high doses These observations, as well as animal studies conducted by

Tiboni, suggest that the teratogenic effects of fluconazole mayin rats and is assigned to risk category C by its manufacturer

[87]. Congenital anomalies have been reported in four infants be dose-dependent [91]. Inman et al. conducted a prescription-

event-monitoring study evaluating the safety of fluconazole inwhose mothers used fluconazole during pregnancy [8890].

Lee and colleagues reported a case of congenital malforma- the treatment of vaginal candidiasis. There was no unusualpattern of fetal abnormalities among 289 women who receivedtion resembling the genetic disorder Antley-Bixler syndrome

in an infant born to a 22-year-old woman receiving fluconazole single or multiple daily doses of fluconazole (150 mg) at some

time before or during pregnancy [92].(400 mg orally once daily) for treatment of disseminated coc-

cidioidomycosis throughout her pregnancy. She experienced More recently, Mastroiacovo and colleagues performed a

prospective assessment of pregnancy outcomes after first-tri-premature rupture of the membranes at 27 weeks gestation

and subsequently underwent cesarean section. mester exposure to fluconazole. They compared 226 women

exposed to this agent (at dosages 150 mg daily) to 452She delivered a premature female infant with grossly dys-

morphic features including radiographic findings of craniosy- women exposed to nonteratogenic agents. They found no dif-

ference in prevalences of miscarriages, congenital anomalies,nostosis, humoral-radial fusion, bowed tibia and femur, and

bilateral femoral fractures. Other findings at autopsy included or low birth weight [93]. It should be noted that, since the

study of Inman et al. [91], every year thousands of pregnanthypoplasia of nasal bones, cleft palate, contractures of both

upper and lower extremities, an incompletely formed right women have inadvertently received fluconazole at daily doses

of 150 mg without untoward effects (Pfizer, Groton, CT;thumb, medial deviation of both feet, shortened toes, crani-

oschisis of the frontal bones, and craniostenosis of the sagittal data on file). This dosage is much lower than the 400 800-

mg daily doses noted in the above case reports.suture. The infant died shortly after birth [88].

Pursley and colleagues reported two similar cases; the first Less information is available concerning itraconazole. To

our knowledge, there have been no reports of its use in humaninfant was born to a 25-year-old woman receiving fluconazole

(800 mg daily) for treatment ofC. immitis meningitis [89]. She pregnancy. Itraconazole has been found to be embryotoxic and

teratogenic in laboratory animals. Teratogenic effects observedbecame pregnant and at 7 weeks gestation was advised to

discontinue therapy. The patient chose to continue therapy included major skeletal defects, encephaloceles, and macro-

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glossia. The manufacturer has assigned itraconazole to risk independent epidemiological investigations [3]. These con-

cerns, and the fact that this drug is not prescribed for life-category C and recommends use of effective contraception for

2 months following treatment [89, 94]. threatening fungal infections, indicate that griseofulvin is best

avoided during pregnancy [4, 86].

Flucytosine

Terbinafine

Flucytosine (5-fluorocytosine, or 5-FC) is a fluorine analogof cytosine. Its usefulness as an antifungal agent is limited to The latest systemic antifungal agent to be marketed is terbi-

nafine, an oral squalene epoxidase inhibitor that is indicatedyeast infections (due toCandida, Cryptococcus,andTorulopsis

species) and is hindered by the prompt development of resis- for onychomycosis of the toenail and fingernail due to dermato-

phytes. Animal studies have revealed no evidence of harm totance [78]. Side effects of this oral medication are common

and can be severe, including gastrointestinal symptoms, hepatic the fetus. To our knowledge, there have been no reports of the

use of terbinafine in pregnancy. The manufacturer has assigneddysfunction, and bone marrow suppression (particularly with

blood concentrations 125 mg/mL). this product to risk category B, but the lack of human data

makes this designation somewhat arbitrary [100].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 thePotassium Iodide

drug is metabolized to 5-fluorouracil, an antineoplastic agent

suspected of causing congenital defects in humans [3]. The Oral potassium iodide remains the treatment of choice for

cutaneous infection caused by Sporothrix schenckii, althoughdrug crosses the human placenta, as evidenced by a case inwhich drug levels in amniotic fluid and mixed cord blood were the triazole drug itraconazole may be useful in this condition

as well [101]. Iodides are generally considered contraindicatedmeasured in a woman with cryptococcal meningitis at 21

weeks gestation. The mother received the drug for only 1 in pregnancy because of their association with congenital goi-

ter, which can be a fatal condition for the newborn. Amongweek prior to elective termination of the pregnancy. A concen-

tration of 168 mg/mL was detected in amniotic fluid 4 hours 49 cases reviewed in 1983, 14 deaths occurred secondary to

tracheal compression [102]. Although short courses used inafter a 2-g oral dosing, and mixed cord blood showed a concen-

tration of 68 mg/mL after the patient had received 4 g that day preoperative management of hyperthyroidism in pregnancy are

reported to be safe [3], the American Academy of Pediatrics[62].

In addition to the above case, three other cases in which and other authorities advise against the use of iodide-containing

drugs during pregnancy [4, 103].flucytosine was used in human pregnancy have been reported

[58, 96, 97]. All were late exposures, with two in the second A single case in which cutaneous sporotrichosis in pregnancy

was treated with potassium iodide has been reported [104].trimester and one in the third. Maternal bone marrow suppres-

sion occurred in one case. No adverse fetal effects were noted. The patient was treated from conception until 2 months priorto delivery, at which time therapy was stopped because ofAlthough the drug is assigned to risk category C by its manu-

facturer, other authorities believe it is contraindicated in preg- concern about possible goiter formation in the infant. The pa-

tient delivered a healthy infant with no evidence of goiter ornancy [73, 86].

thyroid dysfunction. Other cases of cutaneous sporotrichosis

in pregnancy have been treated successfully with the localGriseofulvin

application of heat [105, 106].

Griseofulvin is an organically derived antifungal agent useful

as an oral preparation in the treatment of ringworm. The drugConclusion

is usually well tolerated, although reported side effects include

headache and (rarely) other neurological symptoms, gastroin- Most of the antifungal medications in current use have be-

come available in the past 30 years; nevertheless, experiencetestinal distress, and severe hepatotoxic reactions (the latter in

patients with acute intermittent porphyria). with topical and systemic agents in human pregnancy is limited.

When prescribing medications to pregnant women, it is goodThe drug is embryotoxic and teratogenic in animals exposed

to high doses [98]. In studies by Rubin and Dvormik, griseoful- practice to exercise added caution with recently released medi-

cations. Often a number of years and thousands of exposuresvin was reported to have crossed the human placenta [99].

When given to 12 women prior to cesarean section or induction are required for a particular effect to become evident.

Animal studies, although suggestive, cannot be entirely ex-of labor, drug levels in cord blood ranged from 48% to 100%

of simultaneous maternal blood levels. The FDA has also re- trapolated to human pregnancy. Such was the case with thalido-

mide, a powerful human teratogen that did not produce malfor-ported an association between first-trimester drug exposure and

conjoined twins in two cases, a finding unsupported by two mation in animals. Some effects may be long-delayed in their

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40. Lang WR, Stella JG, Benchakan V. Nystatin vaginal tablets in the treat- 65. Harris RE. Coccidioidomycosis complicating pregnancy:report of 3 cases

and review of the literature. Obstet Gynecol 1966;28:4015.ment of candidal vulvovaginitis. Obstet Gynecol 1956;8:3647.

41. Qualey JR, Cooper C. Monistat cream (miconazole nitrate): a new agent 66. McCoy MJ, Ellenberg JF, Killam AP. Coccidioidomycosis complicating

for the treatment of vulvovaginal candidiasis. J Reprod Med1975;15: pregnancy. Am J Obstet Gynecol1980;137:73940.

1235. 67. Peterson CM, Johnson SL, Kelly JV, Kelly PC. Coccidioidal meningitis

42. McNellis D, McLeod M, Lawson J, Pasquale SA. Treatment of vulvovag- and pregnancy: a case report. Obstet Gynecol1989;73:8356.

inal candidiasis in pregnancy: a comparative study. Obstet Gynecol 68. Gradoni L, Gaeta GB, Pellizer G, Maisto A, Scalone A. Mediterranean

1977;50:6748. visceral leishmaniasis in pregnancy. Scand J Infect Dis 1994;26:

43. Weisberg M. Treatment of vaginal candidiasis in pregnant women. Clin 6279.

Ther1986;8:5637. 69. Dean JD, Wolf JE, Ranzini AC, Laughlin MA. Use of amphotericin B

44. Frerich W, Gad A. The frequency of candida infections in pregnancy during pregnancy: case report and review. Clin Infect Dis 1994;18:

and their treatment with clotrimazole. Curr Med Res Opin 1977; 4: 3648.

6404. 70. Shalev E, Battino S, Romano S, Blondhaim O, Ben-Ami M. Intraamniotic

45. Loendersloot EW, Goormans E, Weisenhaan PE, Barthel PJ, Branolte infection withCandida albicanssuccessfully treated with transcervical

JH. Efficacy and tolerability of single-dose versus six-day treatment amniotransfusion of amphotericin. Am J Obstet Gynecol 1994;170:

of candidal vulvovaginitis with vaginal tablets of clotrimazole. Am J 12712.

Obstet Gynecol 1985;152:9535. 71. Chen C, Wang K. Cryptococcal meningitis in pregnancy. Am J Perinatol

46. Haram K, Digranes A. Vulvovaginal candidiasis in pregnancy treated 1996;13:356.

with clotrimazole. Acta Obstet Gynecol Scand1978;57:4535. 72. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical

47. Tanner GC. Terconazole in the pregnant patient. In: Sobel JD, ed. Clinical experience. Rev Infect Dis1990;12:30829.

perspectives: terconazole, an advance in vulvovaginal candidiasis ther- 73. Bennet JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R,

apy. New York: BMI/McGraw-Hill, 1988:13540. eds. Principles and practice of infectious diseases. 4th ed. New York:

48. Ernest JM. Topical antifungal agents. Obstet Gynecol Clin North Am Churchill Livingstone, 401 10.

1992;19:587607. 74. Fungizone intravenous package insert. Princeton, NJ: ER Squibb and49. Centers for Disease Control and Prevention. 1998 Guidelines for treat- Sons,1993.

ment of sexually transmitted diseases. MMWR1998;47:78. 75. Abelcet package insert. Princeton, NJ: The Liposome Company,1996.50. McGregor JA, Kleinschmidt-DeMasters BK, Ogle J. Meningoencephali- 76. Amphotec package insert. Menlo Park, CA: Sequus Pharmaceuticals,

tis caused by Histoplasma capsulatum complicating pregnancy. Am J 1996.Obstet Gynecol 1986;154:92531. 77. AmBisome package insert. San Dimas, CA: Nextar Pharmaceuticals,

51. Cohen I. Absence of congenital infection and teratogenesis in three chil- 1997.dren born to mothers with blastomycosis and treated with amphotericin 78. Drouhet E, Dupont B. Evolution of antifungal agents: past, present andB during pregnancy. Pediatr Infect Dis J 1987;6:767. future. Rev Infect Dis 1987;9(suppl 1):S414.

52. Hager H, Welt SI, Cardasis JP, Alverez S. Disseminated blastomycosis 79. Graybill JR. Therapeutic agents: the long and short of antifungal therapy.in a pregnant woman successfully treated with amphotericin B. J Re- Infect Dis Clin North Am 1988;2:80525.

prod Med1988;33:4858. 80. Monistat i.v. package insert. Piscataway, NJ: Janssen Pharmaceutica,53. Ismail MA, Lerner SA. Disseminated blastomycosis in a pregnant 1991.

woman: review of amphotericin B usage during pregnancy. Am Rev 81. Nizoral package insert. Piscataway, NJ: Janssen Pharmaceutica,1995.Respir Dis 1982;126:3503.

82. Moriello KA. Ketoconazole: clinical pharmacology and therapeutic rec-54. Neiberg AD, Mavromatis F, Dyke J, Fayyad A.Blastomyces dermatitidis

ommendations. J Am Vet Med Assoc 1986;188:3036.during pregnancy: a case report. Am J Obstet Gynecol 1977;128:83. Sonino N. The use of ketoconazole as an inhibitor of steroid production.

9112.N Engl J Med1987;317:8128.

55. MacDonald D, Alguire PC. Adult respiratory distress syndrome due to84. Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez

blastomycosis during pregnancy. Chest 1990;98:15278.A. Successful treatment with ketoconazole of Cushings syndrome in

56. Aitken GW, Symonds EM. Cryptococcal meningitis in pregnancy treatedpregnancy. Postgrad Med J 1990;66:2213.

with amphotericin B. Br J Obstet Gynaecol 1962;69:6779.85. McGregor JA, Pont A. Contraindication of ketoconazole in pregnancy.

57. Crotty JM. Systemic mycotic infections in northern territory aborigines.Am J Obstet Gynecol 1984;150:7934.

Med J Aust 1965;1:1846.86. Chow AW, Jewesson PJ. Pharmacokinetics and safety of antimicrobial

58. Curole DN. Cryptococcal meningitis in pregnancy. J Reprod Med1981;agents during pregnancy. Rev Infect Dis 1985;7:287313.26:3179.

87. Diflucan package insert. New York: Roerig Division, Pfizer,1996.59. Littman ML. Cryptococcosis (torulosis): current concepts and therapy.88. Lee BE, Feinberg M, Abraham JJ, Murthy ARK. Congenital malforma-Am J Med1959;27:97698.

tions in an infant born to a woman treated with fluconazole. Pediatr60. Feldman R. Cryptococcosis (torulosis) of the central nervous systemInfect Dis J 1992;11:10624.treated with amphotericin B during pregnancy. South Med J 1959;52:

89. Pursley TJ, BlomquistIK, Abraham J, Andersen HF, Bartley JA. Flucona-14157.

zole-induced congenital anomalies in three infants. Clin Infect Dis61. Kuo D. A case of torulosis of the central nervous system during preg-1996;22:33640.nancy. Med J Aust 1962;49:55860.

90. Aleck KA, Bartley DL. Multiple malformation syndrome following flu-62. Stafford CR, Fisher JF, Fadel HE, Espinel-Ingroff AV, Shadomy S,conazole use in pregnancy: report of an additional patient. Am J MedHamby M. Cryptococcal meningitis in pregnancy. Obstet GynecolGenet1997;72:2536.1983;62:35S7S.

91. Tiboni GM. Second brachial arch anomalies induced by fluconazole, a63. Winn WA. The use of amphotericin B in the treatment of coccidioidal

bis-triazole antifungal agent, in cultured mouse embryos. Res Commundisease. Am J Med1959;27:61735.

Chem Pathol Pharmacol 1993;79:3814.64. Hadsall FJ, Acquarelli MJ. Disseminated coccidioidomycosis presenting

92. Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment ofas facial granulomas in pregnancy: a report of two cases and a review

of the literature. Laryngoscope 1973; 83:51 8. vaginal candidiasis: a prescription-event monitoring study, with special

/ 9c5b$$no08 10-14-98 10:30:12 cidas UC: CID


10/10


reference to the outcome of pregnancy. Eur J Clin Pharmacol 1994; 100. Lamisil package insert. East Hanover, NJ: Sandoz Pharmaceuticals,1996.

101. Rex JR. Sporothrix schenckii. In: Mandell GL, Bennett JE, Dolin R,46:1158.

93. Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment of eds. Principles and practice of infectious diseases. 4th ed. New York:

Churchill Livingstone, 23213.pregnancy outcomes after first-trimester exposure to fluconazole. Am

J Obstet Gynecol 1996; 175:1645 50. 102. Mehta PS, Mehta SJ, Vorherr H. Congenital iodide goiter and hypothy-

roidism: a review. Obstet Gynecol Surv 1983;38:23747.94. Sporanox package insert. Piscataway, NJ: Janssen Pharmaceutica,1997.

95. Ancobon package insert. Nutley, NJ: Roche Laboratories,1994. 103. Committee on Drugs, American Academy of Pediatrics. Adverse reac-

tions to iodide therapy of asthma and other pulmonary diseases. Pediat-96. Philpot CR, Lo D. Cryptococcal meningitis in pregnancy. Med J Aust

1972; 2:1005 7. rics 1976;57:2724.

104. Plauche WC. Sporotrichosis in pregnancy. Am J Obstet Gynecol1968;97. Schonebek J, Segerbrand E. Candida albicans septicaemia during first

half of pregnancy successfully treated with 5-fluorocytosine. Br Med 100:11501.

105. Romig DA, Voth DW, Liu C. Facial sporotrichosis during pregnancy.J1973;4:3378.

98. Fulvicin P/G package insert. Kenilworth, NJ: Schering,1996. Arch Intern Med 1972;130:9102.

106. Vanderveen EE, Messenger AL, Voorhees JJ. Sporotrichosis in preg-99. Rubin A, Dvormik D. Placental transfer of griseofulvin. Am J Obstet

Gynecol1965; 92:882 3. nancy. Cutis 1982;30:7613.

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