Risk of congenital malformations and miscarriages following maternal use of oral fluconazole during the first trimester of pregnancy: a systematic review and meta-analysis

IF 7.7 1区医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH European Journal of Epidemiology Pub Date : 2024-12-11 DOI:10.1007/s10654-024-01177-7

Mathilde Latour, Catherine Vauzelle, Elisabeth Elefant, Florence Tubach, Stephanie Padberg, Brigitte Martin, Kristen Joseph-Delaffon, Agnès Dechartres, Benoit Marin

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Abstract

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).

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妊娠前三个月母体口服氟康唑后先天性畸形和流产的风险：一项系统回顾和荟萃分析

妊娠前三个月（T1）使用氟康唑的风险仍然存在争议。本系统综述和荟萃分析的目的是评估T1期口服氟康唑与总体、亚型、轻微畸形和流产之间的关系。我们检索了MEDLINE， EMBASE, Cochrane， ICTRP和ClinicalTrials.gov从成立到24年12月2日。包括随机对照试验和观察性研究。采用ROBINS-I进行偏倚风险评估。固定效应和随机效应模型均进行了meta分析。GRADE用于评估证据的确定性。在1403篇参考文献中，纳入了9项观察性研究（3,764,897例妊娠，其中116,425例暴露于氟康唑）。综合粗略估计（ORc 1.18, 95%CI (1.08-1.29), i223%， 7项研究），T1期间氟康唑使用与总体MCM之间的相关性显著，但结合调整后的估计（ORc 1.02, 95%CI (0.98-1.07), i20%， 6项研究），相关性不显著。结果与氟康唑累积剂量一致。在仅考虑具有有效MCM定义的研究的敏感性分析中，结合调整后的估计，氟康唑150mg与总体MCM之间的关联仍然显著。对于MCM亚型（心脏型、生殖-泌尿型、肌肉-骨骼型），我们没有发现显著的关联。氟康唑的使用与流产之间存在显著关联（比值比1.60,95% CI(1.06-2.42)）。考虑调整后的估计值时，T1期氟康唑的使用并未显著增加MCM总体或亚型的风险。然而，潜在的风险，特别是在累积剂量大于150毫克时，显示出与MCM的潜在关联，值得高度关注。该协议于2021年9月23日注册（注册号：CRD42021274003）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Epidemiology 医学-公共卫生、环境卫生与职业卫生

CiteScore

21.40

自引率

1.50%

发文量

109

审稿时长

6-12 weeks

期刊介绍： The European Journal of Epidemiology, established in 1985, is a peer-reviewed publication that provides a platform for discussions on epidemiology in its broadest sense. It covers various aspects of epidemiologic research and statistical methods. The journal facilitates communication between researchers, educators, and practitioners in epidemiology, including those in clinical and community medicine. Contributions from diverse fields such as public health, preventive medicine, clinical medicine, health economics, and computational biology and data science, in relation to health and disease, are encouraged. While accepting submissions from all over the world, the journal particularly emphasizes European topics relevant to epidemiology. The published articles consist of empirical research findings, developments in methodology, and opinion pieces.