title: Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction.
abstract: OBJECTIVE
  Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?.
  
  
  CONCLUSIONS
  Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche.
  
  
  BACKGROUND
  Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs.
  
  
  METHODS
  In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009.
  
  
  METHODS
  The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high).
  
  
  RESULTS
  In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche.
  
  
  CONCLUSIONS
  We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias.
  
  
  CONCLUSIONS
  Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications.
  
  
  BACKGROUND
  The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests.
  
  
  BACKGROUND
  Not applicable.
authors.affiliation: Danish Ramazzini Centre, Department of Occupational Medicine, Aarhus University Hospital, Norrebrogade 44 Build. 2C, 8000 Aarhus C DK, Denmark.
authors.forename: S L
authors.initials: SL
authors.lastname: Kristensen
authors.forename: C H
authors.initials: CH
authors.lastname: Ramlau-Hansen
authors.forename: E
authors.initials: E
authors.lastname: Ernst
authors.forename: S F
authors.initials: SF
authors.lastname: Olsen
authors.forename: J P
authors.initials: JP
authors.lastname: Bonde
authors.forename: A
authors.initials: A
authors.lastname: Vested
authors.forename: T I
authors.initials: TI
authors.lastname: Halldorsson
authors.forename: G
authors.initials: G
authors.lastname: Becher
authors.forename: L S
authors.initials: LS
authors.lastname: Haug
authors.forename: G
authors.initials: G
authors.lastname: Toft
mesh_terms: D000293:Adolescent; D002210:Caprylates / Q000633:toxicity*; D005260:Female; D005466:Fluorocarbons / Q000633:toxicity*; D005500:Follow-Up Studies; D006801:Humans; D008572:Menarche / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012098:Reproduction / Q000187:drug effects*; D055815:Young Adult
chemical_list: D002210:Caprylates; D005466:Fluorocarbons; C023036:perfluorooctanoic acid
keywords: PFOA; PFOS; female reproduction; menarche; prenatal exposure