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 1403 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, genito-urinary, 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.

PROSPERO Registration The protocol was registered on the 23rd September 2021 (registration number: CRD42021274003).

在妊娠早期 （T1） 使用氟康唑的相关风险仍然存在争议。本系统评价和荟萃分析的目的是评估 T1 期口服氟康唑与主要先天性畸形 （MCM） 之间的总体关联，以及按亚型、轻微畸形和流产的关联。

我们检索了MEDLINE、EMBASE、Cochrane、ICTRP和 ClinicalTrials.gov 检索时间，检索时间从建库到24年12月2日。纳入随机对照试验和观察性研究。ROBINS-I 用于偏倚风险评估。进行了固定效应和随机效应模型荟萃分析。GRADE 用于评估证据质量。

在 1403 篇参考文献中，纳入了 9 项观察性研究（3,764,897 例妊娠，包括 116,425 例暴露于氟康唑）。当合并粗略估计值时，T1 期间使用氟康唑与总体 MCM 之间的相关性是显著的 （ORc 1.18， 95%CI （1.08-1.29）， I² 23%， 7项研究），但当合并调整后的估计值时则不显著 （ORa 1.02， 95%CI （0.98-1.07）， I² 0%， 6项研究）。氟康唑累积剂量的结果一致。在仅考虑具有 MCM 有效定义的研究的敏感性分析中，当合并调整后的估计值时，氟康唑 > 150 mg 与总体 MCM 之间的关联仍然显著。对于 MCM 的亚型 （心脏、生殖泌尿、肌肉骨骼），我们发现没有显着关联。发现氟康唑的使用与流产之间存在显著关联 （ORa 1.60， 95% CI （1.06–2.42）。

在考虑调整后的估计值时，在 T1 期间使用氟康唑不会显著增加总体或亚型 MCM 的风险。然而，潜在风险，特别是累积剂量大于 150 mg 时，显示与 MCM 有潜在关联，值得高度关注。

PROSPERO 注册该方案于 2021 年 9 月 23 日注册（注册号：CRD42021274003）。