Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants
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Anogenital Distance and Perineal Measurements of the Pelvic Organ Prolapse POP Quantification System
Published on: September 20, 2018
B G Fisher1, A Thankamony1, I A Hughes1
1Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Insights
Maternal paracetamol intake during the masculinisation programming window (8-14 weeks gestation) is linked to shorter anogenital distance (AGD) in male infants. This finding suggests potential adverse effects on male reproductive development from prenatal paracetamol exposure.
Area of Science:
- Reproductive Endocrinology
- Developmental Biology
- Environmental Health
Background:
- Increasing male reproductive disorders may be linked to in-utero environmental factors.
- Prenatal paracetamol exposure is suspected to impact fetal testicular development, potentially reducing testosterone production.
- Epidemiological studies suggest associations between prenatal paracetamol and conditions like cryptorchidism.
Purpose of the Study:
- To investigate the relationship between maternal paracetamol use during the masculinisation programming window (MPW) and male infant anogenital distance (AGD).
- To assess AGD as a biomarker for androgen action during fetal development.
- To explore potential adverse effects of prenatal paracetamol on male reproductive development.
Main Methods:
- Prospective cohort study (Cambridge Baby Growth Study) with 24 months of infant follow-up.
- Maternal medicine consumption questionnaires and infant anthropometric measurements (AGD, penile length, testicular descent).
- Linear mixed models used to analyze associations between paracetamol exposure during specific gestational periods and infant outcomes.
Main Results:
- Maternal paracetamol exposure between 8-14 weeks of gestation was significantly associated with shorter infant AGD (0.27 SD reduction, P=0.014).
- This association was independent of infant body size.
- No significant associations were found between paracetamol exposure and penile length or testicular descent.
Conclusions:
- Observational data suggest that intrauterine paracetamol exposure during the critical 8-14 week gestational period may negatively impact male reproductive development.
- Findings support experimental evidence linking prenatal paracetamol to altered fetal testicular function.
- Further research is needed to confirm these associations and explore underlying mechanisms, considering potential confounders.
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?
Summary Answer:
Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.
What Is Already Known:
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.
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.
Participants/Materials, Setting, Method:
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.
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.
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.
Wider Implications Of The Findings:
Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.
Study Funding/Competing Interests:
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.
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