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

B.G Fisher,D.B Dunger,K.K Ong,A Thankamony,C.L Acerini,I.A Hughes

doi:10.1093/humrep/dew196

Abstract

STUDY QUESTIONWhat 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?SUMMARY ANSWERIntrauterine paracetamol exposure during 8–14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.WHAT IS ALREADY KNOWNThe 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.STUDY DESIGN, SIZE, DURATIONProspective 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.PARTICIPANTS/MATERIALS, SETTING, METHODMothers 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.MAIN RESULTS AND THE ROLE OF CHANCEParacetamol 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.LIMITATIONS, REASONS FOR CAUTIONConfounding 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.WIDER IMPLICATIONS OF THE FINDINGSOur observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.STUDY FUNDING/COMPETING INTERESTSThis 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.

Highlights

Male genital disorders at birth and reproductive disorders in adulthood are common, and may be increasing in prevalence (Bay et al, 2006). Skakkebaek et al (2001) proposed that these disorders could arise from foetal Leydig and Sertoli cell dysfunction, resulting in androgen insufficiency and impaired germ cell development—the testicular dysgenesis syndrome (TDS)
Use of a xenograft model demonstrated that administration of paracetamol at the equivalent of a human therapeutic dose for 7 days reduces human fetal testicular testosterone production, another group had previously found no effect of 1–3 days of paracetamol exposure on testosterone production by human foetal testes in vitro (Mazaud-Guittot et al, 2013)
We found no significant association between paracetamol exposure and cryptorchidism at any postnatal time point, our numbers were small (overall prevalence 33/650 (5.1%) at birth and 62/424 (14.6%) at any age)

Summary

Introduction

Male genital disorders at birth (hypospadias and cryptorchidism) and reproductive disorders in adulthood (poor semen quality and testicular germ cell cancer) are common, and may be increasing in prevalence (Bay et al, 2006). Skakkebaek et al (2001) proposed that these disorders could arise from foetal Leydig and Sertoli cell dysfunction, resulting in androgen insufficiency and impaired germ cell development—the testicular dysgenesis syndrome (TDS). Skakkebaek et al (2001) proposed that these disorders could arise from foetal Leydig and Sertoli cell dysfunction, resulting in androgen insufficiency and impaired germ cell development—the testicular dysgenesis syndrome (TDS). Leffers and colleagues were the first to demonstrate that gestational exposure of male rats to paracetamol inhibits masculinisation, through a reduction in testicular testosterone production (Kristensen et al, 2011, 2012). Use of a xenograft model demonstrated that administration of paracetamol at the equivalent of a human therapeutic dose for 7 days reduces human fetal testicular testosterone production (van den Driesche et al, 2015), another group had previously found no effect of 1–3 days of paracetamol exposure on testosterone production by human foetal testes in vitro (Mazaud-Guittot et al, 2013)

Methods

Results

Conclusion