美国布列根和妇女医院和哈佛医学院Yanmin Zhu团队，对孕早期口服氟康唑其胎儿发生先天畸形的风险进行了研究。2020年5月20日出版的《英国医学杂志》发表了这项成果。

为了探讨孕早期口服常用剂量的氟康唑治疗外阴阴道念珠菌病，胎儿发生先天性畸形的风险，研究组进行了一项基于人群的队列研究。对2000-2014年美国医疗补助数据中有关生育保险的一部分进行了分析，招募末次月经3个月前或更久、以及产后不足一月的女性，并招募3个月以上的婴儿。

1969954例妊娠的研究队列包括37650例（1.9％）孕早期口服氟康唑的女性和82090例（4.2％）在孕期外用唑类药物的女性。 每1万例口服氟康唑和外用唑类的的孕妇中，其胎儿发生肌肉骨骼畸形的风险分别为52.1和37.3，发生锥干部畸形的风险分别为9.6和8.3，发生唇腭裂的风险分别为9.3和10.6。

肌肉骨骼畸形倾向评分精细分层后的校正相对危险度为1.30，锥干部畸形为1.04，唇腭裂为0.91。根据氟康唑的累积剂量，150 mg氟康唑的校正后肌肉骨骼畸形、锥干部畸形和唇腭裂的相对风险分别为1.29、1.12和0.88；150-450 mg氟康唑则分别为1.24、0.61和1.08；对于450 mg以上的氟康唑，则分别为1.98、2.30和0.94。

总之，孕早期口服氟康唑与唇腭裂或锥干部畸形无关，但与肌肉骨骼畸形有关。

附：英文原文

Title: Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study

Author: Yanmin Zhu, Brian T Bateman, Kathryn J Gray, Sonia Hernandez-Diaz, Helen Mogun, Loreen Straub, Krista F Huybrechts

Issue&Volume: 2020/05/20

Abstract: Objective To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.

Design Population based cohort study.

Setting A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.

Participants Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.

Interventions Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.

Main outcome measures Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.

Results The study cohort of 1969954 pregnancies included 37650 (1.9%) pregnancies exposed to oral fluconazole and 82090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.

Conclusions Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10000 exposed pregnancies overall.

DOI: 10.1136/bmj.m1494

Source: https://www.bmj.com/content/369/bmj.m1494