Ketoconazole

 Risk Factor: CM
 Class: ANTI-INFECTIVES / Antifungals

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Ketoconazole is a synthetic, broad-spectrum antifungal agent. The antimycotic agent is embryotoxic (1) and teratogenic (1,2) in rats, producing syndactyly and oligodactyly at a dose of 80 mg/g/day (10 times the maximum recommended human dose), a maternally toxic dose. Ketoconazole has been used, apparently without fetal harm, for the treatment of vaginal candidiasis occurring during pregnancy (3).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 20 newborns had been exposed to oral ketoconazole during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (one expected). Since this study, the FDA has received six reports of limb defects (F. Rosa, personal communication, FDA, 1996).

Limb malformations were also reported in a 1985 abstract (4). A Turkish woman had used ketoconazole, 200 mg daily, during the first 7 weeks of gestation. Hydrops fetalis was diagnosed at 29 weeks' gestation and she delivered a female infant at 30.5 weeks'. The infant, with a normal karyotype (46,XX), had multiple anomalies of the limbs (further details not specified).

Women infected with human immunodeficiency virus frequently have vaginal candidiasis. Maternal symptoms, such as pruritus, may require treatment and in these cases, therapeutic and prophylactic ketoconazole regimens are recommended, even though the fungal infection has little perinatal significance (5).

Ketoconazole inhibits steroidogenesis in fungal cells. In humans, high doses, such as those above 400 mg/day, impair testosterone and cortisol synthesis (6,7,8 and 9). Because of this effect, ketoconazole has been used in the treatment of hypercortisolism (10). A review summarizing the treatment of 67 cases of Cushing's syndrome occurring during pregnancy did not find any cases treated with ketoconazole (10). A 1990 report, however, described a ketoconazole-treated 36-year-old pregnant woman with Cushing's syndrome (11). The pregnancy, in addition to Cushing's syndrome, was complicated by hypertension, the onset of gestational diabetes mellitus at 9 weeks' gestation, and intrauterine growth retardation. Ketoconazole, 200 mg every 8 hours, was started at 32 weeks' gestation and continued for 5 weeks because of maternal clinical deterioration resulting from the sustained hypercortisolism. Rapid clinical improvement was noted in the mother after therapy was begun. A growth-retarded, 2080-g, but otherwise normal, female infant was delivered by elective cesarean section at 37 weeks. The Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. No clinical or biochemical evidence of adrenal insufficiency was found in the newborn. The infant's basal cortisol and adrenocorticotropic hormone levels, 306 nmol/L and 8.1 pmol/L, respectively, were normal. The child was growing normally at 18 months of age.

Breast Feeding Summary

No reports describing the use of ketoconazole during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. Although citing no data, the manufacturer states that ketoconazole is probably excreted into milk (1). Moreover, two other azole fungicides (fluconazole and itraconazole) are excreted into breast milk; thus, the passage of ketoconazole into milk should be expected. The effects on the nursing infant from exposure to drug in the milk are unknown.

References

1. Product information. Nizoral. Janssen Pharmaceutics, 1997.
2. Nishikawa S, Hara T, Miyazaki H, Ohguro Y. Reproduction studies of KW-1414 in rats and rabbits. Clin Report 1984;18:143388. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:1075.
3. Luscher KP, Schneitter J, Vogt HP. Frequency of candidiasis during pregnancy and therapy with ketokonazol ovula. Schweiz Rundsch Med Prax 1987;76:12857.
4. Lind J. Limb malformations in a case of hydrops fetalis with ketoconazole use during pregnancy (abstract). Arch Gynecol 1985;237(Suppl):398.
5. Minkoff HL. Care of pregnant women infected with human immunodeficiency virus. JAMA 1987;258:27147.
6. Hobbs ER. Coccidioidomycosis. Dermatol Clin 1989;7:22739.
7. Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C, Stevens DA. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982;97:3702.
8. Engelhardt D, Mann K, Hormann R, Braun S, Karl HJ. Ketoconazole inhibits cortisol secretion of an adrenal adenoma in vivo and in vitro. Klin Wochenschr 1983;61:3735.
9. Divers MJ. Ketoconazole treatment of Cushing's syndrome in pregnancy. Am J Obstet Gynecol 1990;163:1101.
10. Aron DC, Schnall AM, Sheeler LR. Cushing's syndrome and pregnancy. Am J Obstet Gynecol 1990;162:24452.
11. Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A. Successful treatment with ketoconazole of Cushing's syndrome in pregnancy. Postgrad Med J 1990;66:2213.