Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants
Creators: name: Fisher, Benjamin
name: Thankamony, A
name: Hughes, Ieuan
name: Ong, Kenneth
name: Dunger, David
name: Acerini, Carlo
Publisher: name: Apollo - University of Cambridge Repository
Year: 2016
Subjects: paracetamol
testicular dysgenesis syndrome
anogenital distance
testicular descent
endocrine disruption
toxicology

description: ${\bf Study~question:}$ What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW? ${\bf Summary~answer:}$ Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age. ${\bf What~is~known~already:}$ The increasing prevalence of male reproductive disorders may reflect environmental influences on fetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces fetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism. ${\bf Study~design,~size,~duration:}$ Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire. ${\bf Participants/materials,~setting,~methods:}$ Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length, and testicular descent were assessed at 0, 3, 12, 18, and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (&lt;8 weeks, 8-14 weeks, and &gt;14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of 681 male infants were exposed to paracetamol during pregnancy, of whom 68 were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants. ${\bf Main~results~and~the~role~of~chance:}$ Paracetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, p=0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent. ${\bf Limitations,~reasons~for~caution:}$ Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error. ${\bf Wider~implications~of~the~findings:}$ Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.
description: European Union (Framework V programme), World Cancer Research Fund International, Medical Research Council (UK), Newlife Foundation for Disabled Children, Evelyn Trust, Mothercare Group Foundation, Mead Johnson Nutrition, National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre
description: This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Oxford University Press.