Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.
JAMA. 2016 Jan 5;315(1):58-67. doi: 10.1001/jama.2015.17844.
Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information.
To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth.
DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group.
Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.
Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression.
Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).
In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.
阴道念珠菌病在怀孕期间很常见。尽管局部唑类抗真菌药的阴道制剂是孕妇的一线治疗方法，但尽管安全性信息有限，仍常使用口服氟康唑。
研究孕妇口服氟康唑暴露与自然流产和死产风险之间的关系。
设计、地点和参与者：丹麦全国基于登记的队列研究，1997 年至 2013 年。从 1405663 例妊娠队列中，比较了口服氟康唑暴露妊娠与多达 4 例未暴露妊娠，这些妊娠通过倾向评分、母亲年龄、日历年和妊娠年龄（基于有资格的对照者在该日期前的首次治疗的妊娠年龄）进行匹配。为了检验指示性混杂因素，将局部唑类抗真菌药阴道制剂暴露作为额外的比较组。
从国家处方登记处获得口服氟康唑的处方。
使用比例风险回归估计自然流产和死产的危害比（HRs）。
在 3315 名妊娠 7 至 22 周时暴露于口服氟康唑的女性中，147 名发生自然流产，而 13246 名未暴露于匹配女性中 563 名发生自然流产。氟康唑暴露与自然流产风险显著增加相关（HR，1.48；95%CI，1.23-1.77）。在 5382 名妊娠 7 周至分娩时暴露于氟康唑的女性中，21 名发生死产，而在 21506 名未暴露于匹配女性中，77 名发生死产。氟康唑暴露与死产之间无显著关联（HR，1.32[95%CI，0.82-2.14]）。使用局部唑类暴露作为比较，在 2823 名暴露于氟康唑的女性中，130 名发生自然流产，而在 2823 名暴露于局部唑类的女性中，118 名发生自然流产（HR，1.62[95%CI，1.26-2.07]）；在 4301 名暴露于氟康唑的女性中，20 名发生死产，而在 4301 名暴露于局部唑类的女性中，22 名发生死产（HR，1.18[95%CI，0.64-2.16]）。
在这项丹麦全国队列研究中，与未暴露于氟康唑的女性和妊娠期间使用局部唑类的女性相比，妊娠期间使用口服氟康唑与自然流产风险显著增加相关。在更多关于该关联的数据可用之前，谨慎开具氟康唑处方可能是明智的。尽管死产风险没有显著增加，但仍应进一步调查这一结果。
