Prenatal exposure to paracetamol is associated with smaller testis volume and decreased levels of steroid metabolites during infancy in healthy males: A COPANA cohort study of 287 boys

Gylli Mola; Fischer Margit Bistrup; Hanne Frederiksen; Lone Scheel; Wraae Katrine Bak; Rom Ane Lilleøre; Hegaard Hanne Kristine; Kristensen David Møbjerg; Anders Juul; Casper Hagen

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ESPE Abstracts (2024) 98 FC9.4

ESPE2024 Free Communications Sex Endocrinology and Gonads (6 abstracts)

Prenatal exposure to paracetamol is associated with smaller testis volume and decreased levels of steroid metabolites during infancy in healthy males: A COPANA cohort study of 287 boys

Gylli Mola ^1,2 , Margit Bistrup Fischer ^1,2 , Hanne Frederiksen ^1,2 , Lone Scheel ³ , Katrine Bak Wraae ³ , Ane Lilleøre Rom ^4,5 , Hanne Kristine Hegaard ^4,6 , David Møbjerg Kristensen ^1,7 , Anders Juul ^1,2,6 & Casper Hagen ^1,2

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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. ⁴The Department of Obstetrics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. ⁵Research Unit of Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odensen, Denmark. ⁶Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. ⁷Department of Science and Environment, Roskilde University, Roskilde, Denmark

Background: Paracetamol is bought over the counter and frequently used by pregnant women. Studies suggest that paracetamol is endocrine-disruptive, affecting for example germ cell proliferation. Fetal male masculinization is initiated in early gestation (GW 8-14).

Primary aim: To assess if prenatal exposure to paracetamol was associated with testicular function.

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 (n = 685) were enrolled during the first trimester, and 589 (287 boys) infants completed follow-up. Data on maternal paracetamol use was collected retrospectively for three months pre-pregnancy and prospectively every two weeks until the infant examination. This resulted in 12,455 completed questionnaires on intake (yes/no), drug names, and doses (mg). Considering the timing of fetal masculinization, we predefined three exposure groups; Group 0: Unexposed controls (n = 147); 1: GW ≤ 14 (n = 78); 2: GW > 14 (n = 52). Missing data n = 10. The boys were examined (mean age 3.1 months ±0.3SD) including penile size, anogenital distance (n = 287), and testes volume by ultrasound (n = 277). Blood samples (245/287 = 85%) were analyzed for circulating levels of FSH, LH, AMH, Inhibin B (immunoassay), and testosterone as well as a profile of other steroid hormones: 17-OHPreg, 17-OHP, PROG, DOC, CORT, ALDO, 11-DOC, 21-DOC, Cortisol, Cortisone, DHEA, DHEAS, Adione, DHT, E1-2 (LC/MS-MS). Statistics: Student’s T-test or Mann Whitney U test; Group 1 vs. 0 (unexposed controls).

Results: Testis volume and the steroid hormones PROG, 17-OHPreg, and 17-OHP were reduced in boys exposed to paracetamol in early fetal life compared to controls: Group 1 vs. 0; testis volume mean (SD) 402.7 mm³(±86.1) vs. 435.7 mm³ (±103.7), P = 0.023; PROG median (IQR) 0.23 nmol/L (0.19, 0.30) vs. 0.25 nmol/L, (0.22, 0.35), P = 0.012; 17-OHPreg 17.85 nmol/L (10.87, 25.88) vs. 20.80 nmol/L (12.46, 36.39), P = 0.035; and 17-OHP 1.34 nmol/L (1.00, 1.74) vs. 1.59 nmol/L (1.16, 2.17), P = 0.005, respectively. Paracetamol exposure was not associated with other hormone levels, anogenital distance, or penile size.

Conclusion: Testis volume and steroid hormone precursors were reduced in boys exposed to paracetamol in early fetal life. This is the first prospective human study to show that paracetamol negatively affects fetal testicular development, confirming data from previous preclinical studies conducted in experimental animal models.