Paternal use of paracetamol prior to conception is associated with elevated adrenal steroid levels in female infants - a copana study

Emilie Zeuthen; Fischer Margit Bistrup; Gylli Mola; Anna-Maria Andersson; Hanne Frederiksen; Karin Sundberg; Rom Ane Lilleore; Hanne Heggard; Anders Juul; Casper Hagen

doi:10.1530/endoabs.110.P1024

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Endocrine Abstracts (2025) 110 P1024 | DOI: 10.1530/endoabs.110.P1024

ECEESPE2025 Poster Presentations Reproductive and Developmental Endocrinology (93 abstracts)

Paternal use of paracetamol prior to conception is associated with elevated adrenal steroid levels in female infants - a copana study

Emilie Zeuthen ^1,2 , Margit Bistrup Fischer ^1,2 , Gylli Mola ^1,2 , Anna-Maria Andersson ^1,2 , Hanne Frederiksen ^1,2 , Karin Sundberg ³ , Ane Lilleøre Rom ^4,5 , Hanne Heggard ^5,6 , Anders Juul ^1,2,5 & Casper Hagen ^1,2,5

Author affiliations

¹Department of Growth and Reproduction, Copenhagen University Hospital- Rigshospitalet, Copenhagen, Denmark; ²International Center 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; ⁴Research Unit of Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; ⁵Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; ⁶Department of Obstetrics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

JOINT1659

Background: Growing evidence suggest that maternal paracetamol use impairs fetal ovarian development. In animal studies, paternal preconceptional use of paracetamol has been suggested to affect fetal development, possibly through mechanisms including epigenetic changes, altered non-coding RNAs, oxidative stress, or hormonal disruption in the sperm’s paracrine environment. The female HPG and HPA axis is functionally established in early infancy enabling assessment of ovarian and adrenal activity.

Aim: Evaluate associations between paternal use of paracetamol and ovarian and adrenal function in female offspring.

Design: Prospective, observational pregnancy and birth cohort; The Copenhagen Analgesic Study (COPANA) (ClinicalTrials.gov NCT04369222).

Setting: Copenhagen University Hospital – Rigshospitalet, Denmark (2020-2022).

Methods: Healthy, singleton pregnant women enrolled in first trimester of pregnancy (n = 685) and 589 children (302 girls) examined in infancy. Fathers (n = 245) reported their paracetamol use (yes/no) prior to conception and girls were categorized as exposed if their father used paracetamol three months prior to conception (exposed=133, unexposed=112). Girls were examined at age 3.4±0.4 months (mean(±SD) including transabdominal ultrasound: ovarian volume (n = 161/245). Infant serum hormones (n = 218/245): FSH, LH, AMH, Inhibin B (immunoassays), 16 steroid metabolites (LC/MS-MS). Age and sex specific SD-scores were calculated. Mothers reported their paracetamol use every two weeks during pregnancy (yes/no), and delivery mode (vaginal/elective section/emergency section) was obtained from medical records.

Statistics: Mann Whitney U-test and linear regression models.

Results: There was a trend towards reduced ovarian volume; median (IQR) 236.3 mm³ (153.1–419.08) vs 316. 0 mm³ (204.9–458.5) P = 0.069 in exposed girls at infancy compared to unexposed. Furthermore, paternal use of paracetamol was associated with increased levels of several steroid metabolites (Table 1). The associations were not affected after adjusting for maternal use of paracetamol in early pregnancy or delivery mode, respectively. Paternal use of paracetamol was not associated with levels of reproductive hormones in infancy.

.
	Median (IQR)		P-value
	Unexposed (n = 96)	Exposed (n = 122)
17-alpha-hydroxyprogesterone SDS	-0.21 (-0.91– 0.57)	0.09 (-0.66– 0.82)	0.068
11-deoxycortisol SDS	-0.03 (-0.85– 0.60)	0.17 (-0.51– 0.89)	0.047
Cortisol SDS	-0.11 (-0.68– 0.51)	0.27 (-0.45– 0.81)	0.004
11-Deoxycorticosterone SDS	-0.45 (-1.26– 0,48)	-0.08 (-0.87– 0.78)	0.020
Corticosterone SDS	-0.48 (-1.11–0.82)	-0.04 (-0.76– 0.77)	0.035

Conclusion: Paternal paracetamol use before conception appears to affect ovarian development in a manner comparable with effects observed after maternal prenatal use of paracetamol. Furthermore, circulating levels of several adrenal steroids were linked to paternal use of paracetamol. This reinforces concerns about the effects of paracetamol on fetal development, likely involving multiple biological mechanisms.