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 ed 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 Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes. Tweetable Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes.