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 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (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 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 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 10 000 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 10 000 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 10 000 exposed pregnancies overall.

中文翻译：

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头三个月口服氟康唑和先天性畸形的风险：基于人群的队列研究。

目的探讨在妊娠前三个月常用剂量的口服氟康唑接触先天性畸形治疗外阴阴道念珠菌病的风险。设计基于人群的队列研究。根据美国全国医疗补助分析（Medicaid Analytic eXtract 2000-14）的数据，在美国设置了一组公共怀孕保险。参与者从末次月经前三个月或三个月以上至分娩后一个月内登记的Medicaid妇女怀孕，以及出生后三个月或以上的婴儿。干预措施氟康唑和外用唑类药物的使用是通过在怀孕的前三个月中需要一个或多个处方来建立的。主要观察指标肌肉骨骼畸形，圆锥锥状畸形，检查与分娩后头90天内诊断为与口服氟康唑接触有关的口腔裂隙（主要结局）。结果本研究队列的1 969 954例妊娠包括在孕早期暴露于口服氟康唑的37 650例（1.9％）妊娠和局部应用唑类药物的82 090例（4.2％）妊娠。暴露于氟康唑的万例孕妇的骨骼肌肉畸形风险为52.1（95％置信区间44.8至59.3），而暴露于外用唑类的风险为每万孕妇37.3（33.1至41.4）。暴露于氟康唑和外用唑类的每10,000例孕妇发生锥鼻畸形的风险分别为9.6（6.4至12.7）和8.3（6.3至10.3）；每1万例孕妇发生口裂的风险分别为9.3（6.2至12.4）和10.6（8.4至12.8）。肌肉骨骼畸形的倾向评分精细分层后的调整后相对风险为1.30（1.09至1.56），圆锥形鼻畸形为1.04（0.70至1.55），口腔裂隙总体为0.91（0.61至1.35）。根据氟康唑的累积剂量，150 mg氟康唑的经调整的肌肉骨骼畸形，圆锥锥和畸形的相对风险分别为1.29（1.05至1.58），1.12（0.71至1.77）和0.88（0.55至1.40）对于150毫克至450毫克的氟康唑，分别为1.24（0.93至1.66），0.61（0.26至1.39）和1.08（0.58至2.04）; 对于450毫克以上的氟康唑，分别为1.98（1.23至3.17），2.30（0.93至5.65）和0.94（0.23至3.82）。结论妊娠前三个月口服氟康唑与口腔c裂或锥周畸形无关，