Latour Mathilde, Vauzelle Catherine, Elefant Elisabeth, Tubach Florence, Padberg Stephanie, Martin Brigitte, Joseph-Delaffon Kristen, Dechartres Agnès, Marin Benoit
AP-HP.Sorbonne Université, Hôpital Trousseau, Département de Santé Publique, Centre de Référence sur les Agents Tératogènes (CRAT), F75012, Paris, France.
Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Equipe PEPITES, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Centre de Pharmacoépidémiologie (Cephepi), Unité de Recherche Clinique PSL-CFX , F75013, Paris, France.
Eur J Epidemiol. 2024 Dec;39(12):1325-1340. doi: 10.1007/s10654-024-01177-7. Epub 2024 Dec 11.
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), I 23%, seven studies), but not when combining adjusted estimates (ORa 1.02, 95%CI (0.98-1.07), I 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).
孕期头三个月（T1）使用氟康唑的相关风险仍存在争议。本系统评价和荟萃分析的目的是评估T1期口服氟康唑与总体及各亚型的主要先天性畸形（MCM）、轻微畸形和流产之间的关联。我们检索了MEDLINE、EMBASE、Cochrane、ICTRP和ClinicalTrials.gov，检索时间从创建至2024年12月2日。纳入随机对照试验和观察性研究。使用ROBINS - I进行偏倚风险评估。进行了固定效应模型和随机效应模型的荟萃分析。采用GRADE评估证据的确定性。在1403篇参考文献中，纳入了9项观察性研究（3764897例妊娠，其中116425例暴露于氟康唑）。综合粗略估计时，T1期使用任何氟康唑与总体MCM之间的关联具有统计学意义（ORc 1.18，95%CI（1.08 - 1.29），I² 23%，7项研究），但综合调整估计时则无统计学意义（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MCM定义有效的研究的敏感性分析中，综合调整估计时，氟康唑剂量>150 mg与总体MCM之间的关联仍具有统计学意义。对于MCM的亚型（心脏、泌尿生殖、肌肉骨骼），我们未发现显著关联。发现氟康唑使用与流产之间存在显著关联（ORa 1.60，95%CI（1.06 - 2.42））。考虑调整估计时，T1期使用氟康唑总体上或各亚型均未显著增加MCM的风险。然而，潜在风险，特别是累积剂量大于150 mg时显示出与MCM的潜在关联，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）。
