title: Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs.
abstract: Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD)-the distance from the anus to the genitals-in the offspring?
  
  
  
  Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls.
  
  
  
  Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD.
  
  
  
  A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth.
  
  
  
  Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score.
  
  
  
  A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found.
  
  
  
  Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings.
  
  
  
  A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use.
  
  
  
  The study was funded by the Danish Environmental Protection Agency by way of the Center on Endocrine Disruptors Danish Center for Hormone Disrupting Chemicals, the Danish Foundation for Scientific Innovation and Technology (09-067180), the Danish Research Council (4004-00352B_FSS), Novo Nordic Foundation (NNF15OC0017734), Ronald McDonald Children Foundation, K.A. Rohde's and wife's Foundation, Odense University Hospital and Region of Southern Denmark, Municipality of Odense, the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense University Hospital Research Foundation and Odense Patient data Exploratory Network (OPEN). The authors declare they have no competing interests.
  
  
  
  Not applicable.
authors.affiliation: Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Dorte Vesterholm
authors.initials: DV
authors.lastname: Lind
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Main
authors.affiliation: Odense University Hospital, Hans Christian Andersen Children's Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark.|Odense Patient data Exploratory Network (OPEN), Sdr. Boulevard 29, 5000 Odense C, Denmark.
authors.forename: Henriette Boye
authors.initials: HB
authors.lastname: Kyhl
authors.affiliation: Laboratory of Genomic and Molecular Biomedicine, Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen, Denmark.
authors.forename: David Møbjerg
authors.initials: DM
authors.lastname: Kristensen
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, and Department of Pediatrics, Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle Raun
authors.initials: HR
authors.lastname: Andersen
authors.affiliation: Odense University Hospital, Endocrinological Department, 5000 Odense C, Denmark.
authors.forename: Marianne Skovsager
authors.initials: MS
authors.lastname: Andersen
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebæk
authors.affiliation: Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark tkjensen@health.sdu.dk.|Odense University Hospital, Hans Christian Andersen Children's Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark.
authors.forename: Tina Kold
authors.initials: TK
authors.lastname: Jensen
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000627:therapeutic use; D000328:Adult; D001003:Anal Canal / Q000033:anatomy & histology* / Q000187:drug effects; D000700:Analgesics / Q000008:administration & dosage* / Q000627:therapeutic use; D000886:Anthropometry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D005260:Female; D005837:Genitalia, Male / Q000033:anatomy & histology* / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D018811:Maternal Exposure; D009035:Mothers; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen
keywords: acetaminophen; analgesics; anogenital distance; male reproduction; nonsteroidal anti-inflammatory drugs; paracetamol