Prenatal exposure to antifungal medication may change anogenital distance in male offspring: a preliminary study

Abstract

BackgroundVaginal candidiasis is frequent among pregnant women and it is treated with anti-fungal medication (conazoles). Conazoles have anti-androgenic properties and prenatal exposure in rodents is associated with a shorter (less masculine) anogenital distance (AGD) in male offspring. To our knowledge this has never been studied in humans.MethodIn the Odense Child Cohort pregnant women residing in Odense municipality, Denmark, were recruited at gestational age 8–16 weeks between 2010 and 2012. Of the eligible 2421 mother-child pairs, 812 mother-son pairs were included. Questionnaire data on medicine use were collected in first and third trimester and physical examination at age 3 month was performed.Ano-scrotal distance; measured from the centre of anus to the posterior base of scrotum (AGDas). Ano-cephalad distance; measured from the centre of anus to the cephalad insertion of the penis (AGDap) and penile width; measured at the base of the penis.ResultsEighty seven women had used antifungal medicine during pregnancy. Maternal use of oral fluconazole (n = 4) was associated with a 6.4 mm shorter AGDas (95% CI: -11.9;-0.9) in the male offspring. Use of antifungal vaginal tablets (n = 21), was associated with a non-significantly shorter AGDas (−1.9 mm; 95% CI: -4.3; 0.5) whereas exposure to vaginal cream (n = 23) was not associated to AGDas. Use of antifungal medicine in the window of genital development between 8 and 14 weeks of gestation was associated with a larger reduction in AGDas than exposure outside this window. Antifungal medicine intake was not associated with AGDap and penil width.ConclusionOur preliminary findings prompted us to hypothesize that maternal use of conazole antifungal medication during pregnancy may affect the masculinization of male offspring. If confirmed, pregnant women should be advised to use antifungal medicine with caution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-017-0263-z) contains supplementary material, which is available to authorized users.

Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data

“…Exposure to ‘azole’ antifungals that interfere with steroidogenesis may be relevant to pregnancy, given that they are frequently prescribed for the treatment of vaginal candidiasis. No association between maternal use of antifungals and hypospadias has been reported in two studies (Carter et al , 2008) (Norgaard et al , 2008), or for AGD after exposure to antifungals administered as vaginal tablets or as topical cream (Mogensen et al , 2017). However, the latter study demonstrated a significant association between oral fluconazole and reduced AGD in the male offspring (Mogensen et al , 2017).…”

“…No association between maternal use of antifungals and hypospadias has been reported in two studies (Carter et al , 2008) (Norgaard et al , 2008), or for AGD after exposure to antifungals administered as vaginal tablets or as topical cream (Mogensen et al , 2017). However, the latter study demonstrated a significant association between oral fluconazole and reduced AGD in the male offspring (Mogensen et al , 2017). Importantly, for each of these three studies, the numbers of cases was small and larger prospective studies would be required to provide definitive evidence of associations between antifungals and indicators of fetal testosterone production.…”

In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole

“…In humans, maternal use of oral azole anti-mycotic drugs during pregnancy has been associated with anti-androgenic effects such as shorter anogenital distance (AGD) in male offspring (Mogensen et al, 2017). This is supported by several animal studies where, for instance in rodents, prochloraz, tebuconazole and ketoconazole can induce feminization of male offspring, with effects such as increased nipple retention and shorter AGD (Hass et al, 2012;Laier et al, 2006;Taxvig et al, 2008Taxvig et al, , 2007Vinggaard et al, 2005).…”

British Association for Sexual Health and HIV national guideline for the management of vulvovaginal candidiasis (2019)

“…Fluconazole in pregnancy: Given the conflicting evidence below, and the fact that topical therapies are equally effective in the management of VVC, we continue to advise against the use of fluconazole and other oral azoles in pregnancy (Grade 1B): ○A systematic review found that first trimester use of fluconazole does not appear to increase the overall risk of congenital malformation although one study reported a possible link with tetralogy of Fallot 114 ○The United States National Birth Defects Prevention Study (NBDPS) found associations between fluconazole use in the first trimester of pregnancy with cleft lip with cleft palate and d-transposition of the great arteries although overall fluconazole use in the NBDPS was low 115 ○A nationwide register-based cohort study in Denmark (1997–2013) with a cohort of 1,405,500 pregnancies found a statistically significant increased risk of spontaneous abortion in women exposed to fluconazole between 7 and 22 weeks’ gestation compared with risk among unexposed women and women with topical imidazole exposure in pregnancy 87 ○A preliminary study in Denmark with 812 mother–son pairs found that fluconazole exposure in four pregnant women was significantly associated with shorter anogenital distance suggesting a potential anti-androgenic effect. 116 It is important to note that exposure to standard dose fluconazole at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional foetal monitoring. 117 VVC and pregnancy outcome: Previous studies did not find evidence of an association between Candida colonization and premature delivery or low birth weight.…”

“…○A preliminary study in Denmark with 812 mother–son pairs found that fluconazole exposure in four pregnant women was significantly associated with shorter anogenital distance suggesting a potential anti-androgenic effect. 116…”