Antifungal
PREGNANCY RECOMMENDATION: Compatible (Topical)
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Miconazole is normally used as a topical antifungal agent. Small amounts are absorbed from the vagina (1). Use in pregnant patients with vulvovaginal candidiasis (moniliasis) has not been associated with an increase in congenital malformations (1–7). Effects following IV use are unknown. However, one study did find a significant increase in the risk of spontaneous abortions (SABs) with 1st trimester vaginitis treatment (8). A later study speculated that this effect might have been due to inhibition of the critical enzyme aromatase (9). Until there are data on this potential association, the best course is to avoid the use of miconazole 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
Miconazole is in the same antifungal class of imidazole derivatives as butoconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole.
In data obtained from the Michigan Medicaid program between 1980 and 1983, a total of 2092 women were exposed to miconazole during the 1st trimester from a total sample of 97,775 deliveries not linked to a birth defect diagnosis (8). Of 6564 deliveries linked to such a diagnosis, miconazole was used in 144 cases. The estimated relative risk for birth defects from these data was 1.02 (95% confidence interval [CI] 0.9–1.2). An estimated relative risk for SABs of 1.38 (95% CI 1.2–1.5) was calculated based on 250 miconazole exposures among 4264 abortions compared with 2236 1st trimester exposures among 55,736 deliveries. No association was found between miconazole use and oral clefts, spina bifida, or cardiovascular defects. Although the relative risks for total birth defects or the three specific defects were not increased, the authors could not exclude the possibility of an association with other specific defects (8).
In an extension of the above investigation, data were obtained for 229,101 completed pregnancies between 1985 and 1992, in which 7266 newborns had been exposed to miconazole administered vaginally during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 304 (4.2%) major birth defects were observed (273 expected). Specific data were available for six defect categories, including (observed/expected) 77/73 cardiovascular defects, 14/12 oral clefts, 3/4 spina bifida, 22/21 polydactyly, 12/12 limb reduction defects, and 20/17 hypospadias. These data do not support an association between the drug and congenital defects.
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 (9). The authors speculated that the embryotoxicity observed in animals and humans (see also Clotrimazole and Sulconazole) might be explained by inhibition of placental 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 (10). In this case, both the fetus and mother were virilized because of diminished conversion of androgens to estrogen. Because the pregnancy was maintained and because of the virilization, the case suggested that the main function of placental aromatase was to protect the mother and fetus from exposure to adrenal androgens (10).
A 2005 report evaluated the teratogenic potential of vaginal metronidazole + miconazole treatment during the 2nd and 3rd months of pregnancy using the population-based dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996 (11). Their analysis included 21 groups of congenital anomalies. They compared 22,843 women who had newborn infants or fetuses with congenital anomalies (cases) with 38,151 pregnant women who had newborns without defects (controls). Vaginal treatment with the drug combination occurred in 2.5% (576) cases and 2.2% (846) controls. The analysis of cases and their matched controls found an association between the drug combination and poly/syndactyly (21 cases) with an adjusted prevalence odds ratio of 6.0, 95% CI 2.4–15.2. The authors thought that recall bias was unlikely and considered their findings to be a signal, although they had no plausible biological mechanism (11).
BREASTFEEDING SUMMARY
No reports describing the use of miconazole during human lactation have been located. No risk for a nursing infant is expected if the mother is applying the agent topically.
References
1.Product information. Monistat. Ortho Pharmaceutical, 1990.
2.Culbertson C. Monistat: a new fungicide for treatment of vulvovaginal candidiasis. Am J Obstet Gynecol 1974;120:973–6.
3.Wade A, ed. Martindate. The Extra Pharmacopoeia. 27th ed. London: Pharmaceutical Press, 1977:648.
4.Davis JE, Frudenfeld JH, Goddard JL. Comparative evaluation of Monistat and Mycostatin in the treatment of vulvovaginal candidiasis. Obstet Gynecol 1974;44:403–6.
5.Wallenburg HCS, Wladimiroff JW. Recurrence of vulvovaginal candidosis during pregnancy. Comparison of miconazole vs nystatin treatment. Obstet Gynecol 1976;48:491–4.
6.McNellis D, McLeod M, Lawson J, Pasquale SA. Treatment of vulvovaginal candidiasis in pregnancy: a comparative study. Obstet Gynecol 1977;50:674–8.
7.Weisberg M. Treatment of vaginal candidiasis in pregnant women. Clin Ther 1986;8:563–7.
8.Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987;69:751–5.
9.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.
10.Harada N. Genetic analysis of human placental aromatase deficiency. J Steroid Biochem Mol Biol 1993;44:331–40.
11.Kazy Z, Puho E, Czeizel AE. The possible association between the combination of vaginal metronidazole and miconazole treatment and poly-syndactyly population-based case-control teratologic study. Reprod Toxicol 2005;20:89–94.