Antifungal
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Topical econazole does not appear to represent a risk to the human fetus. No teratogenic effects were observed in three animal species following oral and SC dosing that produced systemic exposures far greater than those obtained in humans. The very low systemic bioavailability of this antifungal agent after topical or vaginal application prevents clinically significant amounts from reaching the maternal circulation. Although details of the available human pregnancy experience are incomplete, the risk to an embryo or fetus from the maternal use of econazole appears to be nil. However, one study speculated that antifungals that inhibit placental aromatase, such as econazole, have a potential to cause spontaneous abortions. Until additional data are available on this potential association, the best course is to avoid the use of econazole for vaginitis treatment in the 1st trimester or the application of the antifungal to large areas of skin at any time in pregnancy.
FETAL RISK SUMMARY
Econazole is available only in a topical cream formulation. Vaginal suppositories, spray powder, lotion, and spray solution are available outside of the United States. Econazole is in the same antifungal class of imidazole derivatives as butoconazole, clotrimazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole. It is indicated for the treatment of dermatologic fungal infections including candidiasis. Systemic absorption from the skin or vagina is minimal, with less than 1% of a dose absorbed and recovered in the urine and feces (1–3).
In reproduction studies with oral econazole, no evidence of teratogenicity was observed in mice, rats, or rabbits. Oral doses 10–80 times the human dermal dose, however, did cause embryo and fetal toxicity in some or all members of these species. In addition, prolonged gestation was observed in rats (1). SC doses have also been studied in pregnant mice and rabbits (4). Although no teratogenicity was observed, prolonged gestation and/or fetal death were noted.
It is not known if econazole nitrate crosses the human placenta. The molecular weight (about 445) is low enough, but the amount of drug in the systemic circulation is very low. It is doubtful that clinically significant amounts of the antifungal agent reach the embryo or fetus.
A 1979 report described the use of econazole vaginal suppositories (150 mg at bedtime for 3 days) for the treatment of vaginal candidiasis (5). Some patients required a second course of therapy. Among the patients treated, 24 were pregnant, but the gestational timing of the treatment and pregnancy outcomes were not provided. In a 1981 study, 33 women in various phases of gestation used the same dose and route of administration (6). A second 3-day course of treatment was given to nine of these patients. No details on pregnancy outcomes were reported.
Pregnancy outcome after treatment with a 3-day regimen of econazole vaginal suppositories for vaginal candidiasis was detailed in a 1985 open study (7). Treated were 117 pregnant women with a mean gestational age of 30 weeks (range 10–42 weeks), 44.4% at or after the 36th week of gestation. The number of patients in each trimester was not specified. In 106 pregnancies for which outcome data were available (107 infants, including one set of twins), 13 deliveries were premature. No prolongation of gestation was observed. There were three stillbirths among the 107 infants: one twin; one after intrauterine infection (no fungus recovered); and one death in utero. No congenital defects were observed in the 104 healthy newborns. The mean weight and height were 3301 g and 50.3 cm, respectively. One newborn developed oral thrush, but the mother was still infected at delivery (7).
A 2002 study evaluated azole antifungals commonly used in pregnancy for their potential to inhibit placental aromatase, an enzyme that is critical for the production of estrogen and for the maintenance of pregnancy (8). The authors speculated that the embryotoxicity observed in animals and humans (see also Clotrimazole, Miconazole, and Sulconazole) might be explained by inhibition of aromatase. They found that the most potent inhibitors of aromatase were (shown in order of decreasing potency) econazole, bifonazole (not available in the United States), sulconazole, clotrimazole, and miconazole. However, an earlier study reported a pregnancy that was maintained even when there was severe fetal and placental aromatase deficiency (<0.3% of that of controls) caused by a rare genetic defect (9). In this case, both the fetus and mother were virilized because of diminished conversion of androgens to estrogen. Because the pregnancy was maintained and the virilization, the case suggested that the main function of placental aromatase was to protect the mother and fetus from exposure to adrenal androgens (9).
A population-based case–control study of vaginal econazole in pregnancy was conducted using the Hungarian Case–Control Surveillance of Congenital Abnormalities (10). The study compared 22,843 case women who had newborn infants with a congenital defect with 38,151 controls. Vaginal econazole treatment was used in 68 cases and 122 controls. The crude prevalence odds ratio was 0.9, 95% confidence interval 0.7–1.3 (ns). There also was no evidence that econazole use in the 2nd and 3rd month of pregnancy was associated with teratogenicity (10).
BREASTFEEDING SUMMARY
Although no reports describing the use of topical or vaginal econazole during lactation have been located, the very low systemic bioavailability after topical use suggests that little, if any, of this antifungal will be excreted into breast milk. Therefore, the risk of this exposure to a nursing infant appears to be nil.
References
1.Product information. Spectazole. Ortho-McNeil Pharmaceuticals, 2001.
2.Parfitt K, ed. Martindale. The Complete Drug Reference. 32nd ed. London, UK: Pharmaceutical Press, 1999:377.
3.Econazole Nitrate. Drug Facts and Comparisons. 2000:1612.
4.Maruoka H, Kadota Y, Upshima M, Uesako T, Takemoto Y, Sato H. Toxicological studies on econazole nitrate. 4. Teratological studies in mice and rabbits. Iyakuhin Kenkyu 1978;9:955–70. As cited in Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:189.
5.Lecart C, Claerhout F, Franck R, Godts P, Lilien C, Macours L, Schuerwegh, Longree H, Mine M, Strebelle P, Van Gijsegem M, Wesel S. A new treatment of vaginal candidiasis: three-day treatment with econazole. Eur J Obstet Gynecol Reprod Biol 1979;9:125–7.
6.Karoussos K, Carvalho A, Coelho P, Gomes V, Graca L, Carvalho J, Bacelar Autunes A, Andrade C, Filipe G, Helena Pereira M. Gyno-Pevaryl 150: a new drug for the treatment of vaginal candidosis. J Int Med Res 1981;9:165–7.
7.Goormans E, Beck JM, Declercq JA, Loendersloot EW, Roelofs HJM, van Zanten A. Efficacy of econazole (‘Gyno-Pevaryl’ 150) in vaginal candidosis during pregnancy. Curr Med Res Opin 1985;9:371–7.
8.Kragie L, Turner SD, Patten CJ, Crespi CL, Stresser DM. Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay. Endocr Res 2002;28:129–40.
9.Harada N. Genetic analysis of human placental aromatase deficiency. J Steroid Biochem Mol Biol 1993;44:331–40.
10.Czeizel AE, Kazy Z, Vargha P. A population-based case-control teratological study of vaginal econazole treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2003;111:135–40.