Topical Therapy during Pregnancy

The use of antifungals in the topical treatment of infections of hair, skin, and nails is common. Prescription and over the counter treatments are available for a variety of infections. To date, no topical antifungal treatments have been shown to be teratogenic (causing malformations) during human pregnancy. The use of garlic has been effective and has not been associated with any fetal problems. The use of tee tree oil has not been established as safe during pregnancy. The use of Gentian Violet during pregnancy has not been established as safe.

IMIDAZOLES: COLTRIMAZOLE-(OTC), KETOCONAZOLE-(P) and

MICONAZOLE-(OTC)

Imidazoles are active in treating ringworm, tinea versicolor and other yeast infections. Animal studies have suggested teratogenicity of some imidazoles in high oral doses, but not with topical use. Topical agents are absorbed less by the body when compared to oral preparations and have not been found to be teratogenic. A report on 492 women exposed to various topical azoles (Ketoconazole, Miconazole and Econazole) suggests that Ketoconazole and Miconazole could inhibit testosterone synthesis.  This could potentially inhibit genital development of a male fetus. However, this has not been documented in any controlled studies. Surveillance data from the Michigan Medicaid study reported by Rosa et al, 129 did not find an increased risk for congenital malformations with Miconazole or Clotrimazole use during pregnancy.

AMPHOTERICIN B-(P)

Topical use of Amphotericin B has shown minimal absorption through the skin.

Limited human surveillance data do not indicate any harm to mother or fetus, but relative safety is still unknown.

Vaginal Therapy during Pregnancy

CLOTRIMAZOLE- (OTC)

Clotrimazole is minimally absorbed. The Michigan Medicaid Surveillance study

reported on 1086 pregnancies exposed to Clotrimazole during the first trimester.

There were 74 pregnancies with a birth defect and 112 spontaneous abortions.

These data suggest a slight increase in spontaneous abortions, but no increase in birth defects, with first trimester exposure to Clotrimazole. Clotrimazole is thought to be safe during the second and third trimesters of pregnancy. Czeizel et al 130 studied the possible teratogenicity of Clotrimazole for topical and vaginal therapy using a case-control surveillance study of 18,515 exposed pregnancies during three specific time intervals: first month, second and third month, and fourth through ninth month. Using 32,804

controls, they determined that Clotrimazole use was not associated with an increase in congenital anomalies. Czeizel and Rockenbauer 131 determined that the use of Clotrimazole during pregnancy significantly reduced the incidence of preterm births. These authors suggest that because Clotrimazole effectively treats maternal infection, its use during pregnancy is indicated to eliminate maternal infection associated with prematurity.

MICONAZOLE-(OTC)

Miconazole, one of the most commonly used over the counter yeast infection

medications, is used topically and vaginally. Vaginal use has shown minimal systemic absorption. The Michigan Medicaid surveillance reported on 2236 exposed pregnancies and 144 birth defects. This data does not support a significant increase in fetal malformations above the general population. The same surveillance study reported a

slightly significant increase in spontaneous abortions in women who were prescribed Mconazole 120 days before pregnancy loss, when compared with full term deliveries.

Lack of controlled studies on the safety of Miconazole use during pregnancy, however, does not provide an accurate estimate of potential risk.

NYSTATIN-(OTC)

Nystatin is a polyene antifungal and is available over the counter. Vaginal preparation is the only type of application available due to toxicity by IV or oral administration. Nystatin is poorly absorbed systemically after topical or mucosal application. Specific use of Nystatin has not been studied during pregnancy. Animal studies do not show increased in congenital malformations. 132 Surveillance studies by the Collaborative Perinatal Project and Collaborative Drug Surveillance program did not find an increase of congenital malformation with first trimester use. Of 848 pregnant women, 66 deliveries were linked to birth defects. Surveillance by the Michigan Medicaid study did not show a significant increase in spontaneous abortions in women who were prescribed Nystatin 120 days prior to pregnancy loss when compared to full term deliveries. Although these data do not suggest a risk to human pregnancy, the lack of controlled human studies makes it difficult to establish relative safety.

BUTOCONAZOLE –(OTC)

Butoconazole is minimally absorbed systemically. Clinical trials suggest relative safety with use during the second and third trimesters of pregnancy. However, this data is not from controlled studies, and therefore, Butoconazole should be used with caution during pregnancy.

TIOCONAZOLE-(OTC)

Tioconazole is minimally absorbed systemically. Clinical trials suggest relative safety with use during the second and third trimesters of pregnancy. However, this data is not from controlled studies, and therefore, Tioconazole should be used with caution during pregnancy.

TERCONAZOLE- (P) Terconazole is thought to have negligible systemic absorption.

There is currently no human data to determine safety during pregnancy.

Systemic Therapy during Pregnancy

Systemic (oral/IV) antifungal medications are used to treat serious fungal infections, such as meningitis. Because of their toxicity, use of systemic antifungals during pregnancy is limited to life-threatening infections. Careful consideration of the health of the mother and fetus must be made before their use. Relatively little data exist on the more potent systemic antifungals. However, the triazole class of systemic antifungals (including Fluconazole and Itraconazole) is a less toxic alternative and therefore has been studied more commonly in pregnant women.

TRIAZOLES, ITRACONAZOLE –(P)

Itraconazole is related to Ketoconazole and Fluconazole and is used orally to treat fungal infections. Jick reported on 88 women exposed to oral Itraconazole. When compared to matched controls, Itraconazole exposed women had a relative risk of only 0.6 of having a baby with congenital anomalies. Other data on the use of oral Itraconazole during pregnancy are limited to case reports, which have also failed to suggest an increased risk for fetal birth defects.

FULCONAZOLE-(P) (IV)

Triazole, used to treat systemic fungal infections (Candidiasis, cryptococosis, coccidioiidomycosis and meningitis), penetrates the central nervous system and is

present in high concentrations in the cerebral spinal fluid. Animal studies have shown

teratogenic effects when Fuconazole is administered at high doses. Lee et al reported 3 patients exposed prenatally to Fluconazole.134 These patients showed a pattern of Antley- Bixler-like malformations. Pursley et al reported 3 patients exposed to high oral doses throughout the first trimester.135 These patients exhibited craniofacial, skeletal, and cardiac anomalies. One of the three patients was reported to have the previous diagnosis of Antley-Bixler syndrome.

Antley-Bixler Syndrome:

Antley-Bixler Syndrome includes the following features: brachycephaly, depressed nasal bridge, dysplastic ears, frontal bossing, midfacial hypoplasia, pear shaped nose, proptosis, large anterior fontanelle, long philtrum, craniosynostosis, choanal stenosis/atresia, femoral bowing, radiohumeral synostosis, femoral fracture, thin ribs, multiple contractures, long palms and fingers, camptodactyly, rockerbottom feet, cardiac defects, cleft palate, and early death. Pursley et al concluded that Fluconazole is teratogenic in humans. Kyrieckos et al reported a single patient with fetal exposure to Fluconazole in the first nine weeks. They concluded that Fluconazole is teratogenic and capable of producing Antley-Bixler-like

phenotype. Inman et al studied 60 pregnancies of women with vaginal candidiasis.1 All but one had single oral exposures of 150mg of Fluconazole. No fetal abnormalities were found in any of the 44 live born infants. They concluded that low doses of oral Fluconazole for the treatment of vaginal Candidiasis during pregnancy does not increase the risk for fetal malformations.

Masrroiacovo et al performed a prospective cohort study from the Italian Teratogen Information Service. Of the women exposed to Fluconazole, 90.7% were being treated orally for vaginal candidiasis. The majority of the women were exposed to single low doses of oral Fluconazole during the first trimester. They concluded that single low doses of Fluconazole during the first trimester are not associated with an increased risk for spontaneous abortion, stillbirth, or congenital anomalies. Sorensen et al preformed a retrospective study of 165 women who had received Fluconazole prescriptions just before or during pregnancy and compared them to 13,327 women who did not receive prescriptions.139 Their study found no increase in congenital malformations with single exposures to Fluconazole before conception or during pregnancy. However, this study has many confounding variables, primarily that receiving a prescription does not ensure that the medication was taken. There is a large source of bias in the study.

Jick reports on 234 women of whom 92% were exposed to single 150 mg doses of

Fluconazole.When compared to 492 matched controls, a relative risk of 1.1 for congenital abnormalities was calculated. Three of their patients exposed to high doses exhibited limb deformities that suggested a pattern of malformations. This data suggest possible teratogenicity of Fluconazole.

KETOCONAZOLE-(P)

Numerous problems have been reported with the use of systemic Ketoconazole during pregnancy. It has been shown to be teratogenic and embryotoxic at high doses in animals, with additional data to suggest prolonged gestation. Ketoconazole crosses the placenta and is thought to inhibit gonadal and adrenal steroid synthesis in humans. It has been suggested that Ketoconazole use during pregnancy could inhibit sexual differentiation, although to date there is not human data to prove such an association. Ketoconazole is also used to treat Cushing Syndrome. Two case reports of treatment for Cushing Syndrome are the only data on human exposure during pregnancy. No adverse outcomes were reported. In Amado et al, treatment was administered during the third trimester, when the sex of the fetus was already identified.141 In a second case report, the patient received Ketoconazole therapy from 1-3 weeks and 7-37 weeks of pregnancy. The pregnancy ended in a vaginal delivery at 37 weeks of a normally developed male infant.

From this case report, the authors argue that Ketoconazole is safe to administer during pregnancy. However, lack of data still makes it difficult to establish safety.

MICONAZOLE- (IV)

Miconazole use in IV form has not been studied in human pregnancy. Animal studies do not show teratogenicity in high doses, but it has been reported to be embryotoxic and to prolong pregnancy. Due to limited data, adverse maternal side effects,and the availability of other systemic antifungals, Miconazole should be avoided during pregnancy.

METRONIDAZOLE (P)

Metronidazole is an antimicrobial agent that is primarily used to treat protozoan infections. There has been controversial evidence regarding its use during pregnancy. However, more recent epidemiological studies have led to more conclusive support for its use during pregnancy. Previously, it was hypothesized that Metronidazole could increase the risk for birth defects and possibly for cancer due to its mutagenic capabilities. Olson Robbie et al reviewed the use of Metronidazole in obstetrical practices. Their literature substantiated the fact that Metronidazole crosses the placenta and is found in high concentrations in fetal tissue and amniotic fluid. Their study reports on 597 women exposed to oral Metronidazole during pregnancy for a treatment period of 7 to 10 days.

When compared to 283 untreated controls, there were no significant differences in

stillbirths or prematurity. There was no evidence to suggest teratogenicity. Their paper suggested further studies were needed on the carcinogenesis of Metronidazole. Czeizel and Rockenbauer did a case-control study on the use of oral Metronidazole during the various times of pregnancy. Their data did not suggest an overall increase in congenital abnormalities between cases and controls with second and third month exposures.

              However, certain birth defects were found at a slightly higher incidence in the case populations, and exposure throughout pregnancy did show a slight increase in congenital anomalies. Cleft lip with or without cleft palate and neural tube defects were increased with first month exposures. Poly/syndactyly, anal atresis/stenosis, and hydrocephaly were increased with second and third month exposures, and cardiovascular congenital abnormalities were increased in the case population with exposures between the fourth and ninth months. The authors did suggest that due to the retrospective nature of the study, these findings were possibly due to confounding factors. Caro-Paton et al did a meta-analysis on the teratogenicity of Metronidazole. They looked at all cohort and case-control studies that estimated a risk of congenital malformations after Metronidazole exposure during pregnancy. They concluded that first trimester exposure to

Metronidazole does not significantly increase the risk for congenital abnormalities. The nature of this study did not allow for analysis of specific birth defects. In general, data do not suggest an overall increase in congenital anomalies with Metronidazole use during pregnancy. However, even though some studies examined second and third trimester exposures, there are no data regarding the risk for prematurity, low birth weight, or stillbirth associated with Metronidazole use during that period of pregnancy.

The question of increased cancer risk in children exposed to Metronidazole during

pregnancy has been studied. They studied a retrospective cohort of children under the age of 5. In their study, they did not find an increased risk for tumor development  (leukemia, neuroblastoma, central nervous system tumors, and other cancers), in children exposed prenatally to Metronidazole when compared to non-exposed controls. Further analysis of the carcinogenicity of Metronidazole has not shown an increase in risk for tumor formation in women followed 20 years after treatment for vaginal trichomoniasis.

These findings were based on 771 women, and did not show evidence for mutagenic properties of Metronidazole treatment. Similarly to Clotrimazole, Metronidazole has also been thought to be protective against preterm labor that could be induced by maternal infection. In a placebo controlled trial by McDonald et al, pregnant women using Metronidazole had a significantly reduced risk for preterm labor when compared to the placebo group in two categories: women who previously had experienced preterm labor, and women with previous preterm labor who also had bacterial vaginosis. This study did not find a significant difference between treatment and control populations in women without any history of preterm labor.

FLUCYTOSINE-(P)

Flucytosine is limited to the treatment of yeast infections, and resistance is developed rapidly following treatment. Data suggest that Flucytosine is teratogenic in rats at doses less that the normal human dose. Flucytosine is known to cross the placenta. Case reports of use during the second and third trimesters have not shown adverse outcomes. Flucytosine has the potential to cause congenital defects in humans and is therefore contraindicated in pregnancy.

GRISEOFULVIN-(P)

Griseofluvin is used to treat ringworm. It has been reported to be embryotoxic in

animals and crosses the placenta in humans. There is some suggestion of an association between first trimester exposure and an increased incidence of conjoined twins, but further epidemiological studies failed to support these preliminary findings. Other data regarding the use of Griseofluvin during pregnancy are limited to case reports. These limited findings specifically reported by the FDA might be associated with an increased risk for miscarriage, but this data have not been confirmed by controlled studies.

However, because of limited information, it is suggested that Griseofluvin use be

avoided during pregnancy.

TERBINAFINE-(P)

To date, minimal data are available on the use of Terbinafine for fingernail and toenail infections during pregnancy. Animal studies reveal that there is no evidence for fetal harm. However, there have been no controlled studies on human use during pregnancy.

POTASSIUM IODIDE –(P)

Oral iodides are used to treat cutaneous infections. In general, iodides are thought to be contraindicated in pregnancy because they have been associated with congenital goiter that can be fatal in newborns.

AMPHOTERICIN B -(P)

Amphotericin B is a polyene antifungal that has been used for more than 30 years, with numerous adverse effects (transient azotemia, febrile reactions, shaking chills,

nephrotoxicity, thrombophlebitis, electrolyte disorders and anemia). Amphotericin B is used to treat numerous types of infections including: histoplasmosis, blastomucosis, cryptococcosis, coccidioidomycosis, visceral leishmaniasis, and cryptococcal meningitis.

Oral preparations of Amphotericin B are still the chosen antifungal for severe infections. Amphotericin B is known to cross the placenta and enter the fetal circulation. It is also available in topical form for less severe infections but is minimally absorbed by the skin. Oral/IV formulations of Amphotericin B are commonly prescribed during pregnancy.

Because of the toxicity of Amphotericin B, adverse maternal reactions were commonly reported which included: anemia, acute nephrotoxicity, fever, chills, headache, nausea and vomiting. Fetal effects that were most commonly seen included: anemia, low birth weight, microcephaly, transient acidosis, increased serum creatine levels, respiratory

failure, transient maculopapular rash. Their review of the data concluded that

Amphotericin B is the drug of choice for life threatening fungal infections during

pregnancy. Its use in human pregnancy has not shown consistent adverse fetal effects. Maternal toxicity is common, and pregnant women should be closely monitored if taking Amphotericin B.

Lipid formulations have been more recently introduced into the treatment of

fungal infections especially for women who are intolerant of Amphotericin B.

Abelcet is used for invasive fungal infections. There are currently no human data on its use during pregnancy. Amphotec is prescribed primarily for aspergillosis infections.

Animal studies have not shown detrimental effects to the fetus with 1.1X the human dose.

However, there are currently no data on use during human pregnancy. Ambisome is used to treat febrile neutropenic patients, aspergillus, candida or cryptococcus species and visceral leishmaniasis treatment. Animal studies have shown significantly higher spontaneous abortion rate with 0.5-2X the human dose. One human case report of Ambisome treatment of Mediterranean visceral leishmaniasis (18mg/kg total dose) in a pregnant patient resulted in a normal pregnancy.

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