ESPE Abstracts

Background: Paracetamol is the preferred analgesic and antipyretic during pregnancy. Experimental studies suggest that in-utero exposure to paracetamol disrupts ovarian follicle formation and future ovarian function. This may secondarily affect uterine growth. Female minipuberty is characterized by HPG activity and follicle maturation, however individual levels of reproductive hormones fluctuate considerably.

Primary Aim: The first human cohort study primarily designed to evaluate if prenatal exposure to paracetamol is associated with ovarian function and uterine size.

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. Maternal paracetamol use: collected retrospectively three months prior to pregnancy and prospectively every two weeks (intake: (yes/no), drug name, doses (mg)) (n = 12455 questionnaires). Paracetamol exposure: considering timing of fetal folliculogenesis, four groups were predefined; 0: unexposed (n = 149), 1: <GA 17 (n = 84), 2: GA 17-25 (n = 36), 3: GA 25-birth (n = 33). Dose dependence was assessed by dividing Group 1 into tertiles of doses. Girls examined (age 3.4 months (0.4) mean (±SD)): breast tissue diameter (n = 300), TAUS by single examiner; ovarian volume (n = 189), total follicle count, (n = 192), uterine volume (n = 204). Blood samples (n = 269/302=89%): AMH, FSH, LH, Inhibin B (immunoassays), E2, Androstenedione (LC/MS-MS). Statistics: Mann Whitney U-test, Pearson correlation coefficient.

Results: Uterine volume at minipuberty was reduced in girls exposed to paracetamol in early gestation (<17 weeks); Group 1 vs. unexposed controls: 11.20cm3 (8.66-14.32) median (IQR) vs. 12.56cm3 (9.86-16.37), P = 0.027. There were no associations with ovarian volume, follicle count, breast tissue diameter or circulating levels of reproductive hormones. No associations were found in Group 2 or 3 vs. unexposed. The reduction of uterine volume was even more pronounced in girls exposed within the highest tertile of Group 1 (≥3000 mg of paracetamol) vs. unexposed: 10.88cm3 (8.82-12.55) vs. 12.56cm3 (9.86-16.37), P = 0.020, and there was a tendency of reduced total ovarian follicle count; 1.5 (1.0-2.0) median (IQR) vs. 2.0 (1.0-2.5), P = 0.096. Including all girls, E2 correlated with uterine volume and total follicle count; r =0.148, P = 0.045, r =0.153, P = 0.047, respectively.

Conclusion: Uterine volume was reduced in healthy infant girls exposed to paracetamol in early gestation (<17 weeks). Exposure in later gestation did not have the same effect, hence, timing of exposure seems important. Despite unaffected estradiol levels at a single evaluation during minipuberty, fewer ovarian follicles and reduced sex steroid levels probably explain the reduced uterine size.