Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants.
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?



Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.



The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.



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.



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 (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants.



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.



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.



Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.



This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest.
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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Fisher
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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Thankamony
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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Hughes
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.|MRC Epidemiology Unit, University of Cambridge, Box 285, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
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Ong
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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Dunger
Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK cla22@cam.ac.uk.
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Acerini
D000082:Acetaminophen / Q000008:administration & dosage*; D001003:Anal Canal / Q000033:anatomy & histology* / Q000187:drug effects; D015415:Biomarkers; D001837:Body Weights and Measures; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013737:Testis / Q000033:anatomy & histology* / Q000187:drug effects
D015415:Biomarkers; D000082:Acetaminophen
anogenital distance; endocrine disruption; paracetamol; testicular descent; testicular dysgenesis syndrome; toxicology