ESPE Abstracts

Background: Candidiasis is common in pregnant women. First line treatment for e.g. vulvovaginitis is topical azoles like clotrimazole sold over-the-counter. The mechanism of action is inhibition of CYP51 which is important for synthesis of an essential component of the cell wall (ergosterol), however, azoles inhibit CYP enzyme activity more general.

Aim: In this interdisciplinary study, we assess if fetal exposure to antifungal drugs is associated with steroid hormone levels in infancy. Causal effects as well as potential biological mechanisms are further studied in pertinent experimental models.

Method: Several studies are included: 1) COPANA (ClinicalTrials.gov NCT04369222), a prospective human mother-child cohort (n = 589) including detailed information of maternal medical use during pregnancy reported every two weeks (total 12,455 questionnaires) as well as analyses of circulating steroid hormone profile levels in offspring at infancy (LCMS-MS) + epigenetic analyses of DNA; 2) In-vivo rat study: effects of Clotrimazole and Miconazole exposure to pregnant rats concerning e.g. fetal steroid hormone levels + transcriptome analyses of exposed fetal adrenal tissue; 3) Human fetal adrenal tissue: effects of Clotrimazole and Miconazole exposure concerning steroid hormone levels.

Results: In the human cohort, exposure to antifungal drugs during early fetal life (yes/no) was associated with reduced circulating levels of several steroid hormones in children at 3 months of age. Effects were more profound in boys vs. girls. Estimated fetal weight in 3^rd trimester as well as birthweight were also reduced in exposed males. The causal effect was supported by similar effects in the experimental models. Thus, “confounding by indication” is highly unlikely. Transcriptome analyses as well as epigenetic analyses suggest candidate genes causing the observed effects.

Conclusion: This interdisciplinary study raises concern that early fetal exposure to topical antifungal agents sold over-the-counter causes general inhibition of steroid hormone levels in infancy.