By Rebecca H. Allen, MD, MPH
Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, a Liletta trainer for Actavis, and on the advisory board for Bayer, Actavis, and Vermillion.
SYNOPSIS: In this large cohort study from Denmark, use of oral fluconazole during pregnancy was associated with a slightly increased risk of spontaneous abortion and no increased risk of stillbirth.
SOURCE: Molgaard-Nielsen D, et al. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA 2016;315:58-67.
This is a retrospective cohort study from Denmark that compared the risk of spontaneous abortion (7 through 22 gestational weeks) and stillbirth (≥ 23 weeks) among oral fluconazole-exposed pregnancies to matched controls. The investigators used the country’s Medical Birth Register and the National Patient Register to identify all pregnancies ending with a singleton live birth, stillbirth, spontaneous abortion, or other abortion (ectopic, induced, molar) between Jan. 1, 1997, and Dec. 31, 2013. They were able to link this information by unique personal identifiers to the National Prescription Register and other national databases to obtain data on prescription drug use and other variables, such as age, education, parity, and medical history. Ascertainment of exposure started at gestational week 7 in order to avoid bias from unrecognized early pregnancy losses. Each fluconazole-exposed pregnancy was matched to up to 4 unexposed control pregnancies based on age, calendar year, gestational age, and a propensity score, which determined the probability of fluconazole treatment given all maternal baseline characteristics.
The study included a total of 1,405,663 pregnancies. Among oral fluconazole-exposed pregnancies, 147/3315 (4.43%) spontaneous abortions (SABs) occurred compared to 563/13,246 (4.25%) in the unexposed matched control pregnancies (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.23-1.75). A total of 21/5382 (0.39%) stillbirths occurred in pregnancies exposed to oral fluconazole compared to 77/21,506 (0.36%) unexposed matched pregnancies (HR, 1.32; 95% CI, 0.82-2.14). For the dosage analysis, in the 150-300 mg fluconazole group, there were 132/2986 (4.42%) SABs (HR, 1.4; 95% CI, 1.22-1.77), and in the 350-560 mg group, there were 15/345 (4.3%) SABs (HR, 1.55; 95% CI, 0.94-2.58). Further preplanned sensitivity analyses revealed that timing of fluconazole exposure in pregnancy did not change the results. To control for confounding by indication, a comparison between women prescribed oral fluconazole and topical azoles was conducted. Oral fluconazole-exposed pregnancies experienced 130/2823 (4.6%) SABs compared to 118/2823 (4.2%) topical azole-exposed pregnancies (HR, 1.62; 95% CI, 1.26-2.07). The HRs for SAB were attenuated and not statistically significant when the same mother was compared using a pregnancy exposed to fluconazole and one unexposed.
COMMENTARY
Pregnancy is a risk factor for vulvovaginal candidiasis.1 The Centers for Disease Control and Prevention recommends treating pregnant women with vulvovaginal candidiasis with a 7-day course of topical azoles.2 A longer duration of therapy (7 days vs 1 or 3 days) is typically prescribed in pregnancy. The CDC specifically does not endorse the use of oral fluconazole in pregnancy for vulvovaginal candidiasis due to a lack of safety data (rated FDA pregnancy risk factor category C for single-dose vaginal candidiasis and D for all other indications). Despite this, many practitioners and patients prefer oral dosing to topical vaginal creams during pregnancy. Previous studies have not shown an association between exposure to low-dose oral fluconazole (150 mg) used to treat vulvovaginal candidiasis and birth defects nor with spontaneous abortion or stillbirth.3,4,5 Nevertheless, prior studies of SAB and stillbirth were small, so the investigators conducted the largest study to date on the relationship between oral fluconazole use and pregnancy loss. In the primary analysis, the authors found an almost 50% increased risk of SAB but no increased risk of stillbirth.
The investigators were able to take advantage of Denmark’s national health registries to link data on office visits, hospitalizations, and prescription use in a large group of pregnant women. This makes the study powerful in detecting rare outcomes. I commend the investigators for thinking about possible confounding factors in their study design. Comparing women who took oral fluconazole to topical azoles was very important because these women share the diagnosis of vulvovaginal candidiasis and presumably similar risk factors. However, one could argue that women who received oral fluconazole had more severe infections than those who received topical azoles. The authors also controlled for confounders by comparing fluconazole-exposed pregnancies to women who were using other antibiotics, were hospitalized with infection, or were using antihypertensives; this did not change the results. Nevertheless, the comparisons of women who were treated with fluconazole in one pregnancy and not in another pregnancy resulted in lower HRs and nonsignificant results. The authors acknowledged that this could indicate residual confounding from either a hereditary predisposition to miscarriage or lifestyle factors (smoking and alcohol consumption, for example). Yet, they discounted that because this analysis was based on smaller numbers of exposed individuals than the main analysis (69 subjects vs 147 subjects).
What could be the possible mechanism of action at work here? Fluconazole has not been shown to be teratogenic; therefore, fatal congenital anomalies are not a likely explanation.3 Abortions have been caused in animals using fluconazole, but in much higher doses than those recommended for humans. The authors only speculated that since fluconazole inhibits the fungal CYP51 enzyme, it may also interfere with human CYP450 enzymes that might be important during in utero development. Could the Candida infection itself cause miscarriage and stillbirth? Ascending Candida infection into the uterus causing chorioamnionitis, miscarriage, and preterm delivery is extremely rare but has been described.1 Therefore, it is unclear what the causal pathway would be.
What should be the proper interpretation of this epidemiologic study? The HR of < 2 is not a strong association and indicates susceptibility to bias. Importantly, the within-mother analysis did not show any increased risk of SAB; that would seem to be the best study design because the woman is compared to herself with and without oral fluconazole in pregnancy. My take-home from this article is that there might be a slightly increased risk of miscarriage but it is not certain. It is hard to imagine that a 150 mg dose of oral fluconazole would be powerful enough to cause miscarriage. Nevertheless, I would not prescribe oral fluconazole as first-line therapy for symptomatic vulvovaginal candidiasis in pregnancy anyway. Since topical therapy is an effective alternative to oral dosing, it makes sense to prescribe vaginal treatments first to reduce any unnecessary systemic drug exposure in pregnancy.
REFERENCES
- Aquin TJ, Sobel JD. Vulvovaginal candidiasis in pregnancy. Curr Infect Dis Rep 2015;17:462.
- Centers for Disease Control and Prevention. Sexually Transmitted Diseases 2015 Treatment Guidelines. Available at: http://www.cdc.gov/std/tg2015/default.htm. Accessed Jan. 22, 2016.
- Mølgaard-Nielsen D, et al. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 2013;369:830-839.
- Mastroiacovo P, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996;175:1645-1650.
- Nørgaard M, et al. Maternal use of fluconazole and risk of congenital malformations: A Danish population-based cohort study. J Antimicrob Chemother 2008;62:172-176.
In this large cohort study from Denmark, use of oral fluconazole during pregnancy was associated with a slightly increased risk of spontaneous abortion and no increased risk of stillbirth.
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