Primary Care Corner with Geoffrey Modest MD: Oral Fluconazole in Pregnancy and Spontaneous Abortion: FDA Safety Alert

By Dr. Geoffrey Modest

The FDA just posted a drug safety alert on the use of fluconazole in pregnancy (see http://www.fda.gov/downloads/Drugs/DrugSafety/UCM497705.pdf ), based on a recent JAMA article (see Molgaar-Nielsen D. JAMA2016; 315: 58). Details of the JAMA study:

  • A Danish nationwide registry-based cohort study from 1997-2013, of 1,405,663 pregnancies, looking at the association between oral fluconazole use to treat vaginal candidiasis during pregnancy and spontaneous abortion, and comparing that to use of topical azole antifungals
  • Demographics: 26% were <age 25, 31% age 25-29, 27% 30-34, 13% 35-39; pretty even distribution of household income by quintiles, and pretty equal level of education

Results:

  • 86% had cumulative dose of fluconazole of 150-300mg, first dose at median 69 days of gestation
  • Of 3315 women exposed to oral fluconazole from 7-23 weeks gestation:
    • 147 had a spontaneous abortion, a 48% increase over pregnancies matched on propensity score (a statistical technique used in analysis of observational data which attempts to match cases and controls by accounting for likely covariates/confounders that could affect the results, in this case including maternal age, calendar year, gestational age), with HR 1.48 (1.23-1.77)
  • Of 5382 women exposed to fluconazole from week 7 to birth:
    • 21 had stillbirth, a nonsignificant HR of 1.32 (0.82-2.14) [but pretty small number of events]
  • Use of topical azoles vs fluconazole:
    • 130 of 2823 women given fluconazole vs 118 of 2823 on topical azoles had a spontaneous abortion, a 62% increase associated with fluconazole use, with HR 1.62 (1.26-2.07)
    • 20 of 4301 women given fluconazole vs 22 of 4301 on topical azoles had a stillbirth, a nonsignificant HR 1.18 (0.64-2.16)
  • Further analysis of the spontaneous abortions (all numbers statistically significant):
    • 32% increase within 2 weeks of taking fluconazole; 65% increase after 2 weeks
    • 32% increase in gestational week 7-10 (the vast majority of fluconazole scripts were during this time period), though 90% in gestational weeks 11-22.
    • No statistical difference between lower cumulative dose of fluconazole (150-300mg) vs higher dose (350-5600mg), though small numbers of women at those higher doses

So,

  • The CDC had previously recommended using topical antifungals when treating pregnant women, even if needed for longer periods of time than usual. However, the FDA previously suggested that there did not seem to be an increased risk of problems when women were exposed to a single 150mg dose of fluconazole. But given the above Danish study, theyposted a safety alert suggesting “cautious prescribing of oral fluconazole in pregnancy” while they are completing their review.
  • Vaginal yeast infections are really common in pregnancy: about 10% of pregnant women get them.
  • Although the 48% increase in spontaneous abortions seems large, I am told by statistician types that this level of increase in a retrospective study, even with attempts at propensity matching, may not be found to be significant in a prospective randomized trial. For example, were the women with very severe vaginal candidiasis more likely to get the perhaps bigger gun (oral fluconazole), but in fact it really was the extensive candidiasis that caused the spontaneous abortion? Or potentially T-cell dysfunction which led to the candidiasis and the spontaneous abortion???
  • BUT, a few issues to support the FDA alert:
    • I really doubt there will ever be a formal RCT, since the event rate is small, the number of women needed to be involved would be huge, these are drugs off-patent so drug companies would have little/no interest in paying the rather large cost of a study, and there are more pressing studies for the NIH to fund
    • The study did suggest that the associationfound with fluconazole is not found with the topical azoles
    • And, probably in general, and especially in pregnancy, it probably is better to give topical/local than systemic meds that go right into the blood stream, and then into the fetus
  • So, I think this probably should be a game-changer: to be safe, we should go with the topical azoles in pregnant women with yeast infections…
  • And, as with all of these remarkable huge registry studies done in many western European countries, we in the US stand out again for not having a coherent health care system with systematic registries looking at meds, outcomes, etc. And we do not have universal accessible health care which would allow a registry to get reasonable data from the overall population….

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