Prenatal exposure to paracetamol is associated with smaller testicular volume: a COPANA cohort study of 287 healthy infant boys.
7 affiliations
- 1Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
- 2International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
- 3Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
- 4Department of Gynaecology, Fertility and Obstetrics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
- 5Research Unit of Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
- 6Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
- 7Department of Science and Environment, Roskilde University, Roskilde, Denmark.
Abstract
Study question
Is prenatal exposure to paracetamol associated with testicular function in male offspring?Summary answer
Prenatal paracetamol exposure was associated with smaller testicular volume in infant boys.What is known already
Paracetamol (also known as acetaminophen) is available over the counter and is frequently used by pregnant women. Animal studies and secondary analyses of mother-child cohorts suggest paracetamol can adversely affect testicular development. To our knowledge, this is the first cohort study primarily designed to test the association between prenatal paracetamol exposure and postnatal testicular function.Study design size duration
Prospective, observational pregnancy and birth cohort at a university hospital (2020-2022). Healthy, singleton pregnant women (n = 685) were enrolled during the first trimester, and 589 (287 boys) infants completed follow-up examination at 3 months of age.Participants/materials setting methods
Data on maternal paracetamol use (yes/no and dose) were collected prospectively every 2 weeks throughout pregnancy. Based on the timing of fetal masculinization, participants were classified as exposed at any time during fetal life (n = 137), early exposure (gestational week (GW) ≤ 15; n = 81), late exposure (GW >15; n = 118), or exposed during both early and late fetal life (n = 62). Unexposed boys served as controls (n = 150).The boys were examined at infancy (i.e. minipuberty at mean age 3.1 months ±0.3 SD). Predefined primary outcomes: anogenital distance (AGD), testicular volume, and circulating levels of testosterone.Main results and the role of chance
Across exposure windows, prenatal paracetamol exposure was consistently associated with smaller testicular volume at 3 months of age. Effect estimates were largest in boys exposed at early as well as late fetal life; dose of paracetamol, median (interquartile range (IQR)) 8.5 g (4.0-16.6), testicular volume (β) -34.1 mm³, 95% CI -65.5 to -2.7, P = 0.033.Limitations reasons for caution
Residual confounding by indication cannot be excluded. The generalizability of the study may be affected by the homogeneity of the Copenhagen Analgesic Study (COPANA) cohort. Longitudinal follow-up is necessary for evaluation of reproductive health in adulthood.Wider implications of the findings
In this prospective human cohort study, prenatal paracetamol exposure was associated with reduced testicular volume during minipuberty, a transient period of postnatal activation of the hypothalamic-pituitary-gonadal axis that is considered a critical window for assessing future reproductive function.Funding
Rigshospitalet Research Council supports this work under grants (E-22778-02) and (E-22717-21). The research was furthermore funded by Læge Sofus Carl Emil Friis og hustru Doris Friis'Legat (F-23936-01), Aase og Ejnar Danielsens Foundation (20-10-0367), Helsefonden (20-B-0388), Axel Muusfeldt fond (2020-0385), and The Danish Centre for Endocrine Disrupting Substances (CeHoS) (2022-23219). The publication was completed as part of the MERLON project under grant agreement No. 101137411. The MERLON project is funded by the European Union. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor HADEA can be held responsible for them.Disclosures
D.M.K. has received speaker fees from Merck. A.J. has received speaker fees from Ipsen, Novo Nordisk, and Sandoz. A.J. is Head of Department at a department that has received unrestricted research grants from Novo Nordisk and Lundbeck. All other authors declare no conflicts of interest.Trial registration number
The Copenhagen Analgesic Study (COPANA) (ClinicalTrials.gov NCT04369222).
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BibTeX
@article{mola2026prenatal,
title = {{Prenatal exposure to paracetamol is associated with smaller testicular volume: a COPANA cohort study of 287 healthy infant boys.}},
author = {Gylli Mola and Margit Bistrup Fischer and Hanne Frederiksen and Jørgen Holm Petersen and Lone Scheel and Katrine Bak Wraae and Ane Lilleøre Rom and Hanne Kristine Hegaard and David Møbjerg Kristensen and Anders Juul and Casper P Hagen},
journal = {Human reproduction open},
year = {2026},
month = oct,
doi = {10.1093/hropen/hoag089},
url = {https://europepmc.org/article/MED/42953900},
note = {CC BY},
}
RIS
TY - JOUR
TI - Prenatal exposure to paracetamol is associated with smaller testicular volume: a COPANA cohort study of 287 healthy infant boys.
AU - Gylli Mola
AU - Margit Bistrup Fischer
AU - Hanne Frederiksen
AU - Jørgen Holm Petersen
AU - Lone Scheel
AU - Katrine Bak Wraae
AU - Ane Lilleøre Rom
AU - Hanne Kristine Hegaard
AU - David Møbjerg Kristensen
AU - Anders Juul
AU - Casper P Hagen
PY - 2026
DA - 2026/10/06
JO - Human reproduction open
DO - 10.1093/hropen/hoag089
UR - https://europepmc.org/article/MED/42953900
AB - Study question Is prenatal exposure to paracetamol associated with testicular function in male offspring?Summary answer Prenatal paracetamol exposure was associated with smaller testicular volume in infant boys.What is known already Paracetamol (also known as acetaminophen) is available over the counter and is frequently used by pregnant women. Animal studies and secondary analyses of mother-child cohorts suggest paracetamol can adversely affect testicular development. To our knowledge, this is the first cohort study primarily designed to test the association between prenatal paracetamol exposure and postnatal testicular function.Study design size duration Prospective, observational pregnancy and birth cohort at a university hospital (2020-2022). Healthy, singleton pregnant women (n = 685) were enrolled during the first trimester, and 589 (287 boys) infants completed follow-up examination at 3 months of age.Participants/materials setting methods Data on maternal paracetamol use (yes/no and dose) were collected prospectively every 2 weeks throughout pregnancy. Based on the timing of fetal masculinization, participants were classified as exposed at any time during fetal life (n = 137), early exposure (gestational week (GW) ≤ 15; n = 81), late exposure (GW >15; n = 118), or exposed during both early and late fetal life (n = 62). Unexposed boys served as controls (n = 150).The boys were examined at infancy (i.e. minipuberty at mean age 3.1 months ±0.3 SD). Predefined primary outcomes: anogenital distance (AGD), testicular volume, and circulating levels of testosterone.Main results and the role of chance Across exposure windows, prenatal paracetamol exposure was consistently associated with smaller testicular volume at 3 months of age. Effect estimates were largest in boys exposed at early as well as late fetal life; dose of paracetamol, median (interquartile range (IQR)) 8.5 g (4.0-16.6), testicular volume (β) -34.1 mm³, 95% CI -65.5 to -2.7, P = 0.033.Limitations reasons for caution Residual confounding by indication cannot be excluded. The generalizability of the study may be affected by the homogeneity of the Copenhagen Analgesic Study (COPANA) cohort. Longitudinal follow-up is necessary for evaluation of reproductive health in adulthood.Wider implications of the findings In this prospective human cohort study, prenatal paracetamol exposure was associated with reduced testicular volume during minipuberty, a transient period of postnatal activation of the hypothalamic-pituitary-gonadal axis that is considered a critical window for assessing future reproductive function.Funding Rigshospitalet Research Council supports this work under grants (E-22778-02) and (E-22717-21). The research was furthermore funded by Læge Sofus Carl Emil Friis og hustru Doris Friis'Legat (F-23936-01), Aase og Ejnar Danielsens Foundation (20-10-0367), Helsefonden (20-B-0388), Axel Muusfeldt fond (2020-0385), and The Danish Centre for Endocrine Disrupting Substances (CeHoS) (2022-23219). The publication was completed as part of the MERLON project under grant agreement No. 101137411. The MERLON project is funded by the European Union. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor HADEA can be held responsible for them.Disclosures D.M.K. has received speaker fees from Merck. A.J. has received speaker fees from Ipsen, Novo Nordisk, and Sandoz. A.J. is Head of Department at a department that has received unrestricted research grants from Novo Nordisk and Lundbeck. All other authors declare no conflicts of interest.Trial registration number The Copenhagen Analgesic Study (COPANA) (ClinicalTrials.gov NCT04369222).
SN - 2399-3529
ER -