Mogensen Djamilla Madelung, Pihl Maria Bergkvist, Skakkebæk Niels E, Andersen Helle Raun, Juul Anders, Kyhl Henriette Boye, Swan Shanna, Kristensen David Møbjerg, Andersen Marianne Skovager, Lind Dorte Vesterholm, Jensen Tina Kold
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Winsloewsparken 17 2, 5000, Odense C, Denmark.
Department of Growth and Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Environ Health. 2017 Jun 21;16(1):68. doi: 10.1186/s12940-017-0263-z.
Vaginal 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.
In 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.
Eighty 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.
Our 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.
阴道念珠菌病在孕妇中很常见，通常用抗真菌药物（唑类）治疗。唑类具有抗雄激素特性，啮齿动物在孕期接触该药物与雄性后代较短（雄性特征较弱）的肛门生殖器距离（AGD）有关。据我们所知，这在人类中从未被研究过。
在欧登塞儿童队列研究中，招募了居住在丹麦欧登塞市的孕妇，她们在2010年至2012年期间的孕周为8 - 16周。在符合条件的2421对母婴中，纳入了812对母-子对。在孕早期和孕晚期收集用药问卷数据，并在3个月大时进行体格检查。测量肛门阴囊距离；从肛门中心到阴囊后基部（AGDas）。测量肛门头侧距离；从肛门中心到阴茎头侧插入处（AGDap）以及阴茎宽度；在阴茎基部测量。
87名女性在孕期使用了抗真菌药物。母亲使用口服氟康唑（n = 4）与雄性后代的AGDas缩短6.4毫米相关（95%置信区间：-11.9；-0.9）。使用抗真菌阴道片（n = 21）与AGDas缩短但无统计学意义相关（-1.9毫米；95%置信区间：-4.3；0.5），而接触阴道乳膏（n = 23）与AGDas无关。在妊娠8至14周生殖器发育窗口期使用抗真菌药物与AGDas的更大缩短相关，比在此窗口期之外接触药物的影响更大。抗真菌药物摄入与AGDap和阴茎宽度无关。
我们的初步研究结果促使我们推测，孕妇在孕期使用唑类抗真菌药物可能会影响雄性后代的男性化。如果得到证实，应建议孕妇谨慎使用抗真菌药物。
