The safety of oral fluconazole during the first trimester of pregnancy: a systematic review and meta‐analysis

BACKGROUND: Oral fluconazole is used to treat vulvovaginal candidiasis during pregnancy. However, there are concerns regarding the pregnancy outcomes following exposure to fluconazole. OBJECTIVES: To evaluate the pregnancy outcomes associated with exposure to oral fluconazole during the first trimester of pregnancy. SEARCH STRATEGY: A systematic literature search was conducted to identify relevant studies published from inception until April 2019. SELECTION CRITERIA: Relevant English-language citations using the terms oral fluconazole and pregnancy in humans. DATA COLLECTION: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Oral fluconazole use during the first trimester of pregnancy was marginally associated with an increased risk of congenital malformations (odds ratio [OR] 1.09, 95% CI 0.99-1.2, P = 0.088; n = 6 studies), whereas in the subgroup analysis, this association existed only for high-dose users (>150 mg) (OR 1. 19, 95% CI 1.01-1.4, P = 0.039; n = 2). Exposure to fluconazole also increased the risk of heart malformations (OR 1.31, 95% CI 1.09-1.57, P = 0.003; n = 4), cardiac septal defects (OR 1.3, 95% CI 1.1-1.67, P = 0.047; n = 3), and tetralogy of Fallot (OR 3.39 95% CI 1.71-6.74, P < 0.001; n = 2) in the offspring. In addition, exposure to fluconazole was significantly associated with an increased risk of spontaneous abortion (OR 1.99, 95% CI 1.38-2.88, P < 0.001; n = 3). CONCLUSIONS: Oral fluconazole use during the first trimester of pregnancy appears to be associated with heart malformations and spontaneous abortion, but a causal link cannot be proven. TWEETABLE ABSTRACT: Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes.