EXECUTIVE SUMMARY
In a retrospective analysis of 1.4 million pregnancies in Denmark, use of the oral antifungal medication fluconazole during pregnancy was linked with a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95%CI, 1.23-1.77), compared with risk among unexposed women and women who used a topical antifungal during pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy might be advisable. Although the risk of stillbirth wasn’t significantly increased, this outcome should be investigated further, researchers note.
- Prevalence studies indicate that Candida species colonize the vagina in at least 20% of all women, rising to 30% in pregnancy. Most episodes of symptomatic vulvovaginal candidiasis occur during the second and third trimesters; the increased risk of candidiasis in pregnancy might be linked to pregnancy-related factors, such as immunologic alterations, increased estrogen levels, and increased vaginal glycogen production.
- Topical azole therapies, applied for seven days, are recommended for use among pregnant women.
In a retrospective analysis of 1.4 million pregnancies in Denmark, use of the oral antifungal medication fluconazole during pregnancy was tied to a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95%CI, 1.23-1.77), compared with risk among unexposed women and women who used a topical antifungal during pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy might be advisable. Although the risk of stillbirth wasn’t significantly increased, this outcome should be investigated further.1
Prevalence studies indicate that Candida species colonize the vagina in at least 20% of all women and rises to 30% in pregnancy.2 Most episodes of symptomatic vulvovaginal candidiasis (VVC) occur during the second and third trimesters; the increased risk of VVC in pregnancy might be linked to pregnancy-related factors, such as immunologic alterations, increased estrogen levels, and increased vaginal glycogen production.1
First-line treatment of such infection during pregnancy is topical antifungals via vaginal suppositories, observes Ditte Mølgaard-Nielsen, MSc, an epidemiology researcher at the Statens Serum Institut, Copenhagen, Denmark. However, a small number of pregnant wo-men receive oral treatment with fluconazole despite limited safety information on spontaneous abortion and stillbirth, says Mølgaard-Nielsen, lead author of the current research.
To perform the current study, researchers evaluated the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. The study included 1.4 million pregnancies in Denmark from 1997-2013. From this group, oral fluconazole-exposed pregnancies were compared with up to four unexposed pregnancies, matched on maternal age, calendar year, and gestational age. Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.
Among 3,315 women exposed to oral fluconazole from seven 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 (hazard ratio [HR], 1.48; 95% confidence interval (CI), 1.23-1.77). Among 5,382 women exposed to fluconazole from gestational week seven 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]), researchers note. Using topical azole exposure as the comparison, 130 of 2,823 women exposed to fluconazole versus 118 of 2,823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]. Twenty of 4,301 women exposed to fluconazole versus 22 of 4,301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).1
“Previous safety studies have focused on possible teratogenic effects associated with use of oral fluconazole in pregnancy (lower doses), because five case reports have linked long-term, high-dose fluconazole treatment in pregnant women to a distinct pattern of birth defect,” states Mølgaard-Nielsen. “Until now there has only been two smaller observational studies investigating spontaneous abortion and stillbirth and with a total of 1,500 pregnant women treated with oral fluconazole.”
CHECK THE OPTIONS
According to the Centers for Disease Control and Prevention’s (CDC) 2015 Sexually Transmitted Diseases Treatment Guidelines, the diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritus, pain, swelling, and redness. Clinicians should look for such signs as vulvar edema, fissures, excoriations, and thick curdy vaginal discharge. Diagnosis can be made in a woman who has signs and symptoms of vaginitis in two ways:
- a wet preparation (saline, 10% potassium hydroxide [KOH]) or Gram stain of vaginal discharge that demonstrates budding yeasts, hyphae, or pseudohyphae;
- a culture or other test that yields a positive result for a yeast species.3
According to the guidance from the CDC, only topical azole therapies, applied for seven days, are recommended for use among pregnant women.
Most organizations, such as the American College of Obstetricians and Gynecologists and the CDC, have advised against or caution with using fluconazole in pregnancy given concerns about adverse effects on the fetus, says Jeanne Marrazzo, MD, MPH, FACP, FIDSA, professor of medicine in the Division of Allergy and Infectious Diseases and adjunct professor in the Department of Global Health at the University of Washington. The Food and Drug Administration (FDA) warned in 2011 that chronic use of oral fluconazole in high doses (400-800 mg/day) during the first trimester of pregnancy might be associated with certain birth defects in infants. In issuing the warning, the FDA recommended that healthcare professionals counsel patients if the drug is used during pregnancy or if a patient becomes pregnant while taking the drug.
“We typically recommend topical (vaginal) clotrimazole or a similar agent in this setting,” says Marrazzo, who also serves as medical director of the University of Washington STD Prevention Training Center.
There are no formal studies evaluating the use of long-term suppressive maintenance oral azoles in the treatment of recurrent vulvovaginal candidiasis in pregnancy. Most clinicians don’t offer suppressive therapy in pregnancy and opt to treat individual symptomatic episodes only using a topical imidazole vaginally for seven days to minimize systemic exposure to medications.1
REFERENCES
- Mølgaard-Nielsen D, Svanström H, Melbye M, et al. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA 2016; 315(1):58-67.
- Aguin TJ, Sobel JD. Vulvovaginal candidiasis in pregnancy. Curr Infect Dis Rep 2015; 17(6):462.
- Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64(No. RR-3):1-137.
