Drugs in Pregnancy and Lactation: Tenth Edition

CLOTRIMAZOLE

Antifungal

PREGNANCY RECOMMENDATION: Compatible

BREASTFEEDING RECOMMENDATION: Compatible

PREGNANCY SUMMARY

The absorption of clotrimazole from the skin and vagina is minimal. Three large surveillance studies found no association between clotrimazole and birth defects. However, one study did find a significant increase in the risk of spontaneous abortions (SABs) with 1st trimester vaginitis treatment. A later study speculated that this effect might have been due to inhibition of the critical enzyme aromatase. Until there are more data regarding this possible association, the best course is to avoid the use of clotrimazole 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

Clotrimazole is in the same antifungal class of imidazole derivatives as butoconazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole. No reports linking the use of clotrimazole with congenital defects have been located. The topical use of the drug in pregnancy has been studied (14). No adverse effects attributable to clotrimazole were observed. Absorption of the agent from the skin and vagina is minimal (5).

Suspected birth defect diagnoses occurred in 6564 offspring of 104,339 women in a retrospective analysis of women who had delivered in Michigan hospitals during 1980–1983 (6). First-trimester vaginitis treatment with clotrimazole occurred in 74 of the 6564 deliveries linked to birth defect diagnoses and in 1012 of the 97,775 cases not linked to such diagnoses. The estimated relative risk of birth defects when clotrimazole was used was 1.09 (95% confidence interval [CI] 0.9–1.4). An estimated relative risk for SABs of 1.36 (95% CI 1.1–1.6) was calculated based on 112 clotrimazole exposures among 4264 abortions compared with 1086 1st trimester exposures among 55,736 deliveries. Although an increased relative risk for birth defects was not found, this study could not exclude the possibility of an association with a specific birth defect (6).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 2624 newborns had been exposed to clotrimazole (maternal vaginal use) during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 118 (4.5%) major birth defects were observed (112 expected). Specific data were available for 6 defect categories, including (observed/expected) 27/26 cardiovascular defects, 4/4 oral clefts, 3/1 spina bifida, 9/7 polydactyly, 1/4 limb-reduction defects, and 6/6 hypospadias. These data do not support an association between vaginal use of clotrimazole and congenital defects.

Data from the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980–1992) were used to examine the potential teratogenic effects of vaginal and/or topical use of clotrimazole (7). Although clotrimazole use was not associated with an increase in the prevalence of any birth defect (fetal and live births), there was a suggestion that it was associated with a decrease in the prevalence of undescended testis (prevalence odds ratio 0.72, 95% CI 0.54–0.95) (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 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 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).

BREASTFEEDING SUMMARY

The absorption of clotrimazole from the skin and vagina is minimal (5). Therefore, it is doubtful if measurable amounts of the antifungal agent appear in milk.

References

1.Tan CG, Good CS, Milne LJR, Loudon JDO. A comparative trial of six-day therapy with clotrimazole and nystatin in pregnant patients with vaginal candidiasis. Postgrad Med 1974;50(Suppl 1):102–5.

2.Frerich W, Gad A. The frequency of Candida infections in pregnancy and their treatment with clotrimazole. Curr Med Res Opin 1977;4:640–4.

3.Haram K, Digranes A. Vulvovaginal candidiasis in pregnancy treated with clotrimazole. Acta Obstet Gynecol Scand 1978;57:453–5.

4.Svendsen E, Lie S, Gunderson TH, Lyngstad-Vik I, Skuland J. Comparative evaluation of miconazole, clotrimazole and nystatin in the treatment of candidal vulvo-vaginitis. Curr Ther Res 1978;23:666–72.

5.Product information. Lotrimin. Schering, 2000.

6.Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987;69:751–5.

7.Czeizel AE, Toth M, Rockenbauer M. No teratogenic effect after clotrimazole therapy during pregnancy. Epidemiology 1999;10:437–40.

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 Bi ol 1993;44:331–40.