Babies whose mothers used common azole antifungal medicines during pregnancy, mostly over-the-counter creams and vaginal tablets, had measurably different adrenal hormone levels at three months of age than unexposed infants, according to a Danish study highlighted Oct. 6 by the Technical University of Denmark (DTU). The hormone values stayed within the normal range, and the researchers say the work cannot show that the drugs caused the differences, but they argue the safety of these widely used products in pregnancy deserves closer study.
The peer-reviewed paper was published July 31 in Communications Medicine, a Nature Portfolio journal, and was brought to wider attention by the October release. It combined three lines of evidence: a prospective cohort of 589 Danish mother-child pairs, laboratory experiments on human fetal adrenal tissue, and studies in pregnant rats. The work was led by Copenhagen University Hospital (Rigshospitalet) and the DTU National Food Institute, with partners at IRSET in France. Gylli Mola of Rigshospitalet and Monica Kam Draskau of DTU are co-first authors.
In the cohort, 36 children had been exposed to antifungals before 15 weeks of gestation and 53 from 15 weeks onward, compared with 409 unexposed children, according to the paper’s figure legends. Models were adjusted for maternal pre-pregnancy body mass index, parity and maternal paracetamol use. The timing of exposure appeared to matter. Early-pregnancy exposure was associated with lower circulating steroid hormone levels and signs of reduced androgen action, including smaller penile width in infancy. Exposure in mid-to-late pregnancy was associated with higher steroid levels and a longer anogenital distance, a marker of prenatal androgen exposure, in female fetuses and male infants.
The experimental work pointed the same way. Clotrimazole reduced progesterone in cultured human fetal adrenal tissue and in exposed rats, and miconazole increased anogenital distance in rat offspring, the abstract states. Pregnant rats received miconazole at 35 or 70 mg per kilogram a day or clotrimazole at 25 or 75 mg per kilogram a day from gestational day 7 to 21. The team also reported 358 differentially expressed genes in the adrenal glands of exposed rat fetuses and 262 differentially methylated DNA regions, mapping to 237 genes, in exposed infants.
Terje Svingen, a professor at the DTU National Food Institute, said the use of these medicines “appears to affect adrenal hormone levels in children long after birth,” while noting that “the hormone levels remained within the normal range.” Mola, a researcher and physician at Rigshospitalet, said the treatments recorded in the cohort were “primarily over-the-counter topical preparations, such as creams and vaginal tablets.” Draskau, who worked on the experimental analyses, said the laboratory results “strengthens our hypothesis that there is a link with the use of azole-based antifungal medicines.”
The study was funded by the Danish Environmental Protection Agency through the Danish Centre on Endocrine Disrupters, the Rigshospitalet Research Council and the EU-funded MERLON project. The authors declared no conflicts of interest.
Why it matters
Azole antifungals are sold without a prescription, and in this cohort 89 children were classified as exposed during pregnancy, so the question applies to a routine, not exotic, exposure. The authors note that fetal exposure to endocrine-disrupting chemicals has been linked to reproductive disorders, which is why they tracked anogenital distance and penile measurements alongside hormone levels. Their conclusion is that commonly used antifungals may alter fetal adrenal steroid production and reproductive development, with effects that persist after birth, and that the safety of topical azoles in pregnancy may need re-evaluation.
For clinicians and pregnant patients, the researchers’ own framing is cautious. They cannot conclude that the antifungals are harmful to children, and the hormone differences were within the normal clinical range. Nothing in the study changes current prescribing advice; anyone with questions about a medicine in pregnancy should raise them with their doctor or midwife.
The caveats
The human component is observational, so it cannot establish cause and effect. The exposed groups were small, 36 children in the early window and 53 in the later one, and the figure legends show results flagged at a significance threshold of p of 0.05 or less, with trends reported between 0.05 and 0.1, which raises the risk of chance findings across many outcomes. The rat experiments used daily doses of 25 to 75 mg per kilogram and the human adrenal tissue was exposed at a concentration of 1 micromolar; how these compare with exposure from creams and pessaries is not addressed in the abstract. Effect sizes and confidence intervals are not reported there either. Whether the hormone differences affect children’s later health or fertility is unknown, the DTU release says. The paper appeared in July; the October release recirculated it rather than reporting new data.
What to watch
The authors call for further research into the safety of widely used antifungals during pregnancy. Longer follow-up of the Danish cohort would show whether the hormone and anatomical differences persist beyond infancy, and whether they have any bearing on puberty or fertility.
This article is for general information and does not replace advice from a qualified clinician. Corrections: email the editor using the address on the Contact page.
