The risks related to fluconazole use during the first trimester of pregnancy (T1) remain controversial.

The aims of this systematic review and meta-analysis were to assess the association between oral fluconazole during T1 and major congenital malformations (MCM) overall and by subtype, minor malformations and miscarriages.

We searched MEDLINE, EMBASE, Cochrane, ICTRP and ClinicalTrials.gov from inception to 02/12/24. Randomized controlled trials and observational studies were included. ROBINS-I was used for risk of bias assessment. Both fixed-and random-effects models meta-analyses were performed. GRADE was used to assess the certainty of the evidence.

Among 1,403 references, nine observational studies were included (3,764,897 pregnancies, including 116,425 exposed to fluconazole). The association between any fluconazole use during T1 and overall MCM was significant when combining crude estimates (ORc 1.18, 95%CI (1.08-1.29), I² 23%, seven studies), but not when combining adjusted estimates (ORa 1.02, 95%CI (0.98-1.07), I² 0%, six studies).

Results were consistent for cumulative dose of fluconazole. In sensitivity analyses considering only studies with a valid definition of MCM, the association between fluconazole >150 mg and overall MCM remained significant when combining adjusted estimates. For the subtypes of MCM (cardiac, genitourinary, musculoskeletal) we found no significant association. A significant association was found between fluconazole use and miscarriages (ORa 1.60, 95% CI (1.06-2.42).

Fluconazole use during T1 does not significantly increase the risk of MCM overall or by subtype when considering adjusted estimates. However, potential risks, particularly at cumulative doses greater than 150 mg which show a potential association with MCM, deserve much attention.