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

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 Moth...

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

“…Thus, there is a significant male-female difference in AGD by 11-13 weeks' gestation (54), which is fully developed by 17-20 weeks (26,54). Moreover, fetal exposure to painkillers, which has been shown to suppress testosterone production by the fetal human testis (55), is associated with reduced AGD in boys (56,57), and this may be restricted to exposures during 8-14 weeks' gestation (56).…”

Anogenital distance and reproductive outcomes in 9‐ to 11‐year‐old boys: the INMA‐Granada cohort study

“…Specifically, epidemiological studies published over the past few years have suggested that prenatal exposure to antiandrogenic compounds, such as phthalates, dioxins, and bisphenol A, may be associated with shortened AGD in children (Bustamante‐Montes et al ., ; Miao et al ., ; Papadopoulou et al ., ; Swan, ; Swan et al ., ; Vafeiadi et al ., ). More recently, a shorter AGD has also been associated with the intake of certain analgesics during pregnancy (Fisher et al ., ; Lind et al ., ).…”

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

“…However, these results do not show a paracetamol-only induced effect and this may highlight the importance of exposure to ‘mixtures’ potentially resulting in additive effects which may be more representative of analgesic intake during pregnancy 36. A similar study (n=434 male infants) reported an association between paracetamol exposure and reduced AGD from birth to 2 years which was independent of body size37 and interestingly, this association was limited to paracetamol exposure during the proposed human MPW (ie, first trimester). Importantly, all of the above epidemiological studies are based on self-reporting of analgesic use, determined in most cases by the use of retrospective questionnaires.…”