Just one or two oral doses of fluconazole (Diflucan, Pfizer, and generics) for vaginal candidiasis during pregnancy was not associated with significantly increased risks of stillbirth or neonatal death, a new Scandinavian cohort study shows.
Matched analysis of nationwide register data from more than 1.4 million pregnancies in Sweden and Norway shows that, when compared with pregnancies not exposed to oral fluconazole, there was no significant difference in the risk of stillbirth or neonatal death following exposure at either high or low doses.
A report on the study, led by Björn Pasternak, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, was published online June 12 in the Journal of the American Medical Association.
Results show there were 2.7 stillbirths per 1000 fluconazole-exposed pregnancies and 3.6 per 1000 unexposed pregnancies (hazard ratio, 0.76). And there were 1.2 neonatal deaths per 1000 exposed pregnancies and 1.7 per 1000 unexposed pregnancies (relative risk, 0.73).
These findings "were similar for doses of 300 mg or less and for more than 300 mg," the study authors write, although they note that the number of pregnancies exposed to higher doses of fluconazole (> 300 mg) was small.
This study is twice the size of a previous Danish study, and may be the first to report an outcome of neonatal death, the investigators say. Nevertheless, more research is still needed to guide clinical practice, they emphasize.
"Although the data on fluconazole use in pregnancy suggests no increased risk of stillbirth, additional studies should be conducted and the collective body of data scrutinized by drug authorities before recommendations to guide clinical decision-making are made and weighed against the benefits of therapy," they advise.
In the US, 4% of Pregnant Women Use Oral Fluconazole for Thrush
As previously reported by Medscape Medical News, the use of fluconazole for the treatment of vaginal candidiasis during pregnancy remains controversial, particularly at doses higher than those commonly used to treat thrush (150 mg administered once or twice).
In spite of this, about 4% of pregnant women in the United States use oral fluconazole, the study authors note.
For the study, Pasternak and colleagues used nationwide register data to identify all pregnancies with singleton live births and stillbirths in Sweden, from July 2006 to December 2014, and in Norway, from January 2005 to December 2015.
Pregnancies with a prescription for fluconazole in the 28 days prior to conception were excluded, as were pregnancies with a prescription for any nonfluconazole oral azole anti-fungal in the period extending from 28 days before conception to delivery.
The final cohort was made up of 1,485,316 pregnancies, including 852,959 in Sweden and 632,357 in Norway.
Stillbirth was defined as fetal loss after 22 weeks' gestation. However, in Sweden from July 2006 until June 2008, stillbirth was defined as fetal loss after 28 completed weeks. Neonatal death was defined as that occurring in the first 27 days following birth.
Filled prescriptions were analyzed to determine a history of any fluconazole exposure at any stage of pregnancy. Outcomes by fluconazole dose were also examined.
Fluconazole-exposed and unexposed pregnancies were matched 1:10 based on age. Propensity scores were estimated for each country's dataset.
The researchers created a distinct matched cohort for analyses of stillbirth (based on live births and stillbirths), and a similar one for neonatal deaths (based on live births). Gestational day at fluconazole exposure was used as a matching criterion.
Data from both countries were pooled for analysis, although the sensitivity analyses carried out in Sweden included a broader set of covariates in the propensity score, the researchers point out.
FDA Warned Low Doses for Yeast Infections Might Cause Miscarriage
The US Food and Drug Administration issued a safety alert for oral fluconazole during pregnancy in April 2016 following the publication of a Danish study that showed one or two doses of 150 mg oral fluconazole during 7 to 22 weeks' gestation raised the risk of miscarriage by 48%.
That study's findings also indicated the risk for spontaneous abortion was increased by 62% in women treated with low-dose oral fluconazole compared to women treated with topical azoles, as reported by Medscape Medical News.
Those researchers also found a trend toward a higher risk for stillbirths among women who took oral fluconazole compared with unexposed matched controls or unexposed unmatched pregnant women, but these differences were not statistically significant.
But the current study investigated twice the number of fluconazole-exposed pregnancies in two countries compared with the earlier Danish study, Pasternak and colleagues point out.
The study was supported by the Thrasher Research Fund, Magnus Bergvall Foundation, and Karolinska Institutet Research Foundation. Pasternak and colleagues have reported no relevant financial relationships.
JAMA. Published on June 12, 2018. Research letter
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Cite this: Oral Fluconazole for Thrush in Pregnancy Doesn't Up Stillbirth - Medscape - Jun 12, 2018.