ABSTRACT: Whether common doses of oral fluconazole used in treating fungal infections of the skin or mucous membranes increase the risk of specific birth defects remains a concern. The teratogenic potential of oral azole antifungal agents is important because pregnant women are at increased risk for vaginal candidiasis, the most common clinical indication for these drugs. This registry-based, nationwide cohort study evaluated the association between first-trimester oral fluconazole exposure and the risk of major birth defects.
Using a nationwide cohort of all live-born infants born between 1996 and 2011, data were obtained on prescriptions for oral fluconazole, itraconazole, and ketoconazole that were filled by the cohort women during their pregnancies. Unexposed women were those who did not fill prescriptions for oral azole antifungal agents during the first trimester. The 15 specific birth defects previously associated with azole antifungal agents were craniosynostosis, cleft palate, cleft lip with or without cleft palate, other craniofacial defects, middle ear defects, limb defects, limb reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects, tetralogy of Fallot (TOF), pulmonary artery hypoplasia, ventricular septal defects, and hypoplastic left heart. Chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, congenital viral infections associated with malformations, and minor defects were excluded. Prevalence odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression for each exposure category and each birth defect outcome. Primary analyses included any exposure to fluconazole or exposure to different fluconazole doses and the outcome of either birth defects overall or birth defects linked with azole antifungal agents. Categories of cumulative doses during the first trimester were 150, 300, and 350 to 6000 mg, based on the standard treatment of vaginal candidiasis. Secondary analyses included exposure to itraconazole and ketoconazole and the outcome of birth defects overall.
A total of 976,300 live-born infants were included in the study. No significantly increased risk of birth defects overall was observed among 7352 pregnancies exposed to any fluconazole, as compared with 968,236 unexposed pregnancies (adjusted prevalence OR, 1.06; 95% CI, 0.92–1.21); evaluation of exposure using the cumulative doses did not change this result. No significantly increased risk was found for 14 of the defects, with the only exception being TOF. Based on 7 exposed pregnancies, the risk of TOF was 3 times higher (prevalence 0.10%) than that among 287 unexposed pregnancies (prevalence, 0.03%; adjusted prevalence OR, 3.16; 95% CI, 1.49–6.71). Similar results were observed when the 15 birth defects were evaluated according to cumulative fluconazole dose. No significantly increased risk of birth defects overall was observed among the 687 and 72 pregnancies exposed to itraconazole and ketoconazole, respectively, and no clustering of malformations was observed.
Exposure to any oral fluconazole or to the described cumulative doses during the first trimester of pregnancy was not associated with significantly increased risks of birth defects overall, nor was exposure to oral itraconazole or ketoconazole. The only birth defect at higher risk was TOF, but the absolute risk was small. However, this association should be confirmed in future studies.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark