An analysis by Danish investigators published in JAMA shows that taking oral fluconazole during pregnancy is associated with a significant increased risk of spontaneous abortion. Concern had been raised regarding the drug’s safety in pregnant women after case reports linked long-term, exposure to high-dose fluconazole with craniofacial and skeletal birth defects.
Data for the study came from the Medical Birth Register, which contains record of all Danish births, and the National Patient Register, which contains records of all outpatient and inpatient hospital contacts in Denmark. The cohort used by the researchers included all pregnancies ending with singleton live birth, stillbirth, spontaneous abortion, and other abortive outcomes between January 1, 1997 and December 31, 2013. Women who filled oral fluconazole prescriptions before pregnancy onset were excluded from the study.
To limit immortal time bias (a downward bias caused by an artificially low risk of early spontaneous abortions) of very early exposure to oral fluconazole in pregnancy, the specific time windows of exposure and non-exposure in the analyses of spontaneous abortion and stillbirth were gestational weeks 7 to 22 and week 7 to birth, respectively. To control for cofounders, each exposure pregnancy was matched with up to four similar unexposed control pregnancies based on maternal age, gestational age, calendar year, and propensity scores. Cases of spontaneous abortion were defined as pregnancy loss from gestational week 7 to week 22 and cases of stillbirth were defined as pregnancy loss from week 23.
The total cohort consisted of 1,405,663 pregnancies. In the 3315 pregnancies exposed to fluconazole from weeks 7 to 22, there were 147 spontaneous abortions. In the 13246 unexposed matched control pregnancies, there were 563 spontaneous abortions. Fluconazole exposure compared with nonexposure among matched control pregnancies was associated with a significantly higher risk of spontaneous abortion (HR, 1.48; 95% CI 1.23-1.77). A similar risk was observed in unmatched, unexposed pregnancies (HR, 1.49; 95% CI 1.27-1.75).
In the 5382 pregnancies exposed to fluconazole from week 7 to birth, 21 stillbirths occurred. In the 21506 unexposed matched pregnancies, 77 stillbirths occurred. There was not a significant increased risk in this subcohort; for fluconazole-exposed pregnancies vs unexposed, matched pregnancies, the HR was 1.32 (95% CI, 0.82-2.14). For fluconazole-exposed pregnancies vs unexposed, unmatched pregnancies, the HR was 1.44 (95% CI, 0.94-2.21).
In sensitivity analysis for spontaneous abortion, HRs associated with fluconazole doses of 150 mg to 300 mg (standard treatment dosages) and with doses of 350 mg to 5600 mg (higher treatment dosages used for more complicated infections) were 1.47 (95% CI, 1.22-1.77) and 1.55 (95% CI, 0.94-2.58), respectively, (P = .84). For stillbirth sensitivity analysis, the HRs associated with low and high doses were 0.99 (95% CI, 0.56-1.74) and 4.10 (95% CI, 1.89-8.90), respectively. Oral fluconazole-exposed pregnancies were at a significantly increased risk of spontaneous abortion compared with topical azole-exposed pregnancies (130/2823 vs 118/2823, respectively; HR, 1.62 [95% CI, 1.26-2.07]) and compared with pivmecillinam-exposed pregnancies (140/3018 vs 143/3018, respectively; HR, 1.44 [95% CI, 1.14-182]).
The authors mentioned a few strengths and limitations of their study. Among the noted strengths was the large, nationwide cohort of all registered births and abortions across a 17-year span. They also used filled prescriptions to determine exposure and outcome. Among the study’s limitations was the inability to capture very early spontaneous abortions since not many are recognized clinically.
Although oral fluconazole use in pregnancy was associated with an increased risk of spontaneous abortion in this analysis, the association between drug exposure and risk of stillbirth was not as significant. However, the researchers pointed out that this subcohort was quite small and the outcome relatively rare, which could signify imprecise results and indicated that more research is necessary.