A 2021 review article examines the use of common antifungal drugs during pregnancy. Many pregnant women with fungal infections may require systemic therapy; however, oral antifungals such as fluconazole, itraconazole, and griseofulvin have been linked to birth defects and spontaneous abortions in some reports. Animal studies indicate potential fetal risk, and controlled studies in pregnant women are limited or lacking. The authors note that evidence suggests low-dose fluconazole (150 mg/day) may carry some fetal risk, but in specific situations, such as life-threatening infections or when alternative treatments are ineffective, the benefits may outweigh the risks. Higher doses of fluconazole (400-600 mg/day) appear to carry a greater risk of adverse fetal outcomes. Systemic azoles, including fluconazole and itraconazole, are fungistatic drugs shown to be teratogenic and embryotoxic in animal models, causing craniofacial and rib abnormalities. Observational studies in humans suggest that fluconazole exposure during pregnancy may be associated with spontaneous abortions, congenital heart defects (including cardiac septal defects), and musculoskeletal malformations such as abnormal skull development, oral clefts, bowed long bones, thin ribs, muscle weakness, and joint deformities. Population-based studies reinforce these findings. One cohort of nearly 2 million pregnancies found that first-trimester oral fluconazole exposure was associated with a modestly increased risk of musculoskeletal malformations compared with topical azoles, with an adjusted relative risk of 1.30 and an absolute risk increase of about 12 per 10,000 pregnancies. Other studies suggest potential links to cardiac malformations, including tetralogy of Fallot. Meta-analyses and systematic reviews indicate that these risks appear dose-dependent: higher doses (>150 mg) are linked to increased risk of cardiac defects, limb abnormalities, and spontaneous abortion, whereas lower doses (≤150 mg) appear relatively safer. [1]
A 2024 systematic review and meta-analysis investigated the potential risks associated with the use of oral fluconazole during the first trimester of pregnancy. The analysis included data from 9 observational studies, encompassing a total of 3,764,897 pregnancies with 116,425 women exposed to fluconazole to assess the association between fluconazole exposure and the occurrence of major congenital malformations (MCM) and miscarriages. Results highlighted a significant association between fluconazole exposure of any dose in the first trimester of pregnancy and overall MCM when considering crude odds ratios (ORc 1.18, 95% CI 1.08-1.29). However, this association was not apparent in analyses using adjusted odds ratios (ORa 1.02, 95% CI 0.98-1.07), suggesting that confounding factors may influence the outcomes. A significant crude association for risk of MCM was noted between doses ≤ 150 mg (ORc 1.12, 95% CI 1.04-1.19) and doses > 150 mg (ORc 1.22, 95% CI 1.06-1.40). Despite these findings, the certainty of evidence ranged from very low to low, underscoring the need for further research to confirm these associations and guide clinical decision-making. The study calls for standardized definitions and methodologies to improve the reliability and comparability of future investigations into the teratogenic risks of fluconazole.[2]
A 2021 meta-analysis evaluated the teratogenic potential of maternal fluconazole use during pregnancy by analyzing 9 studies encompassing 53,407 fluconazole-exposed pregnant women compared to 3,319,353 unexposed women. This meta-analysis aimed to provide further clarity regarding the association between fluconazole exposure during the first trimester and congenital malformations in offspring. Dosing was stratified based on low dose (≤ 150 mg), high dose (> 150 mg), or any exposure (any dose). Results indicated that maternal exposure to fluconazole was associated with an increased risk of heart defects in offspring for both low-dose (OR 1.95, 95% CI 1.18-3.21; p= 0.01) and any dose exposure (OR 1.79, 95% CI 1.18-2.71; p= 0.01). Notably, no significant difference was observed between high-dose fluconazole versus control (OR 3.13, 95% CI 0.53-18.61; p= 0.21). However, this comparison involved high-heterogeneity (I2= 97.7%) and more limited data from 3 studies. The meta-analysis also explored other types of malformations and outcomes, revealing no significant associations between fluconazole exposure (low-dose, high-dose, or any exposure) and risks of spontaneous abortion, stillbirth, or other major congenital malformations such as orofacial, musculoskeletal, central nervous system, gastrointestinal, and genitourinary defects. Despite these findings, the substantial heterogeneity observed in heart defect analyses (I2 = 80.2% for low-dose and I2 = 82.8% for any-dose) underscores the complexity of fluconazole's teratogenic potential. [3]
Another 2020 systematic review and meta-analysis investigated fetal outcomes following maternal exposure to oral antifungal agents during pregnancy. The review included 8 cohort studies and one case-control study. The studies predominantly involved oral fluconazole and itraconazole used during pregnancy. In total, data were analyzed from 14,534 pregnancies exposed to fluconazole and 1,311 exposed to itraconazole, focusing on birth defects, spontaneous abortion, and stillbirth outcomes, and incidence rates were compared to values for the general population published by EUROCAT. Data from 4 case control studies revealed that oral fluconazole exposure during pregnancy may slightly increase the risk of congenital heart defects (frequency 1.52% vs. 0.77% for general population) and limb defects (0.62% vs. 0.56%). In contrast, oral itraconazole exposure might heighten the risk of eye defects. However, the study found no significant overall increase in the risk of other birth defects, spontaneous abortions, or stillbirths in comparison to non-exposed groups. One case control study compared fluconazole exposed women to control women, finding fluconazole exposure during the first trimester was significantly associated with cleft palate (OR, 5.53; 95% CI 1.68-18.24) and dextro-transposition of the great arteries (OR 7.56; 95% CI 1.22-35.45). Despite these findings, the authors suggest that the risks associated with fluconazole and itraconazole necessitate further cautious investigation, especially concerning specific birth defects. In this study, effects were not stratified based on fluconazole dose due to inadequate data. [4]