Maternal fluconazole use during the third trimester and risk of QT prolongation in the offspring

Abstract Introduction Oral fluconazole is widely prescribed during pregnancy for fungal infections, particularly in persistent vaginal candidiasis, when topical treatment fails. While generally considered safe, fluconazole is known to prolong the QT interval and potentially increase the risk of ventricular arrhythmias. Due to its prolonged half-life in neonates of 55–88 hours maternal fluconazole exposure may cause neonatal QT prolongation, though this has not been investigated. Purpose To investigate whether third-trimester maternal fluconazole exposure is associated with neonatal QT prolongation and other electrocardiographic (ECG) traits. Methods This study is part of a large general population-based cohort who had neonatal cardiac investigations performed. Neonates were included in this study if they had an available ECG. Fluconazole exposure was defined as at least one filled maternal prescription for fluconazole during the third trimester identified through the National Prescription Registry. The primary outcome was the corrected QT-interval (QTc), calculated using Bazzet’s (QTcBaz) and Fredericia (QTcFri) formulas. ECG parameters were presented with 2nd and 98th percentiles and visualized through boxplots (see Figure 1). Exposed neonates were compared with unexposed neonates using the Wilcoxon Rank-Sum Test. Results Among 16,857 neonates with available ECGs, 62 were exposed to fluconazole during the third trimester (56.5% male, median gestational age 40.6 weeks IQR 39.1–41.3, age at ECG 11 days IQR 6.3–14.0). These were compared to 16,371 non-exposed neonates (51.4% male, median gestational age 40.1 weeks IQR 39.1–41.0, age at ECG 11 days IQR 7.0-14.0). Neonates exposed to fluconazole had significantly prolonged QTc intervals (QTcBaz: 423 ms vs. 419 ms and QTcFri: 366 ms vs. 364 ms, both p 0.01) compared to non-exposed neonates. Both groups had similar heart rate (HR) (139 bpm vs. 143 bpm, p 0.05). A significant difference was also observed in S-V6 amplitude and QRS duration (p 0.01). No significant differences were found in any other ECG parameters (all p 0.05, see Table 1). Conclusion Third-trimester maternal fluconazole use was associated with prolonged Qtc intervals compared to non-exposed neonates, suggesting a potential in utero effects on cardiac electrophysiology.