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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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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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glossia. The manufacturer has assigned itraconazole to risk category C and recommends use of effective contraception for 2 months following treatment [89, 94].

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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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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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