Maternal urinary paracetamol is associated with reduced uterine size and breast tissue diameter at infancy: a COPANA cohort study of 302 healthy girls

Fischer Margit Bistrup; Gylli Mola; Hanne Frederiksen; Karin Sundberg; Rom Ane Lilleore; Hegaard Hanne Kristine; Anders Juul; Hagen Casper P

doi:10.1530/endoabs.110.P995

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Endocrine Abstracts (2025) 110 P995 | DOI: 10.1530/endoabs.110.P995

ECEESPE2025 Poster Presentations Reproductive and Developmental Endocrinology (93 abstracts)

Maternal urinary paracetamol is associated with reduced uterine size and breast tissue diameter at infancy: a COPANA cohort study of 302 healthy girls

Margit Bistrup Fischer ^1,2 , Gylli Mola ^1,2 , Hanne Frederiksen ^1,2 , Karin Sundberg ³ , Ane Lilleøre Rom ^4,5 , Hanne Kristine Hegaard ^4,6 , Anders Juul ^1,2,6 & Casper P Hagen ^1,2,6

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; 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

JOINT2822

Background: Maternal self-reported use of paracetamol during early pregnancy is associated with impaired ovarian function and reduced uterine size in female offspring. A single study reported urinary paracetamol (U-paracetamol) levels above 4000 ng/mL post-consumption – remaining over 1000 ng/mL for up to two days. However, no standardized cutoff for recent use exists. An alternative source of paracetamol is Aniline (textiles and pesticides), which is metabolized in the liver to paracetamol. Due to potential recall bias in self-reported data, urinary paracetamol levels may offer a more objective exposure assessment.

Aim: The first study evaluating associations between maternal U-Paracetamol measurements and ovarian activity in offspring.

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

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

Methods: Healthy, singleton pregnant women, enrolled in first trimester of pregnancy (n = 685), 589 infants (302 girls) examined. All pregnant women provided a urine sample in gestational week 14.1 (1.8) mean (±SD). Urinary levels of total paracetamol (free and conjugated) were measured (LC-MS/MS) and adjusted for urinary osmolarity. To ensure sufficient statistical power, girls whose maternal U-paracetamol levels exceeded 1500ng/mL (n = 21) were defined as highly exposed. Girls examined (age 3.4 months (0.4) mean (±SD)): breast tissue diameter (n = 300), ovarian volume (n = 203), total follicle count, (n = 203), uterine length (n = 257) and volume (n = 230) by transabdominal ultrasound. Blood samples (n = 269/302=89%): AMH, FSH, LH, Inhibin B (immunoassays), E2 (LC/MS-MS).

Results: Paracetamol was measurable in all urine samples median (IQR) 64.5ng/mL (34.6-141.8), 14/21 women with U-paracetamol >1500ng/mL reported use of paracetamol in the first trimester. Uterine length and volume as well as breast tissue diameter were reduced in girls highly exposed to paracetamol in early fetal life; maternal U-paracetamol ≥1500ng/mL vs. <1500ng/mL, uterine length: 22.5 cm (20.4-26.7) vs. 25.5 cm (23.6-27.4) median (IQR) P = 0.012, uterine volume: 9.7 cm³ (8.0-11.8) vs. 12.2 cm³ (9.8-15.1), P = 0.038, mamma tissue diameter: 8. 0 mm (0-10.6) vs. 9. 6 mm (7.1-11.9), P = 0.049. Additionally, there was a trend towards reduced ovarian volume: 2.1 cm³ (1.39-3.47) vs. 2.8 cm³ (1.7-4.5), P = 0.095.

Conclusions: Including novel, objective assessment of paracetamol exposure in early fetal life, high levels of maternal U-paracetamol was associated with reduced sizes of estradiol-targeted organs, specifically the uterus and breast tissue. A trend of smaller ovarian volume suggests lower estradiol production, though single estradiol measurements showed no clear association, possibly due to individual fluctuations during minipuberty. Despite relying on a single U-paracetamol evaluation, findings align with self-reported data, reinforcing concerns about maternal paracetamol use affecting offspring ovarian function.