• A Ernst, S L Kristensen, G Toft, A M Thulstrup, L B Håkonsen, S F Olsen, and C H Ramlau-Hansen.
• Department of Occupational Medicine, Aarhus University Hospital, Noerrebrogade 44, build 2C, Aarhus C DK-8000, Denmark. andern@rm.dk
• Hum. Reprod. 2012 Dec 1; 27 (12): 3593-600.

Study QuestionDoes in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health?Summary AnswerIn utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women.What Is Known AlreadyStudies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear.Study Design, Size And DurationA prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008.Participants/Materials, Setting And MethodsThe pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable.Main Results And The Role Of ChanceWe observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed.Limitations And Reasons For CautionWe collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle.Wider Implications Of The FindingsThis study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function.Study Funding/Competing Interest(S)Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

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