Summary:
Female reproductive health is strongly influenced by events that occur during fetal development. Females are born with a finite number of ovarian follicles, which form before birth and gradually decline throughout life until menopause. The establishment of this follicle pool depends on pregnancy, and may be particularly vulnerable to environmental and pharmaceutical exposures. Paracetamol is one of the most commonly used medications during pregnancy, with more than half of pregnant women reporting its use. As the drug crosses the placenta, concerns have been raised about its potential effects on fetal reproductive development. Animal studies have consistently shown that prenatal paracetamol exposure can reduce ovarian follicle reserves and impair fertility in female offspring. However, evidence from human studies has remained limited. This prospective observational cohort study investigated whether prenatal paracetamol exposure was associated with markers of ovarian function in infant girls. The study included 302 daughters, where maternal paracetamol exposure was assessed during pregnancy. Ovarian and uterine development, reproductive hormone levels, and other indicators of reproductive function were then assessed during infancy. Findings were also examined in an independent cohort of 1,210 girls followed from infancy into adolescence. This study found that prenatal paracetamol exposure was associated with several indicators of altered reproductive development. Exposure during early fetal life was linked to smaller ovarian and uterine volumes, while exposure later in pregnancy was associated with fewer ovarian follicles. Girls exposed only during early fetal development also showed lower concentrations or certain hormones. Higher maternal urinary paracetamol levels were associated with reduced ovarian size, uterine size, and breast tissue measurements. As this is an observational study, causality cannot be confirmed, however the findings do suggest that prenatal paracetamol exposure may be associated with changes in early ovarian development.
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Abstract:
STUDY QUESTION Is fetal exposure to paracetamol associated with markers of ovarian function in infancy? SUMMARY ANSWER Mild to moderate doses of prenatal paracetamol exposure, assessed by detailed maternal reports and urinary measurements, are associated with ovarian morphology and activity as well as reduced size of estrogen-responsive tissues in infant girls. WHAT IS KNOWN ALREADY Maternal use of paracetamol is widespread. Across multiple independent animal studies, fetal exposure consistently impairs the formation of primordial ovarian follicles, causing subfertility and premature estropause in female offspring. STUDY DESIGN, SIZE, DURATION The Copenhagen Analgesic study (COPANA) is a single-center, prospective, observational cohort study conducted at a university hospital (March 2020 to November 2022). From 3425 eligible participants, 685 healthy singleton pregnant women of Caucasian origin, were enrolled in the first trimester of pregnancy, and 302 infant daughters were examined at follow-up. Exclusion criteria included maternal diabetes or thyroid disease, pre- or post-term delivery, or severe infant illness. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnant women reported paracetamol use biweekly and provided first-trimester urinary samples which were analyzed for paracetamol levels (LC-MS/MS) and adjusted for urinary osmolarity (n = 299). Girls were classified by timing of initial exposure: early fetal life (<17 weeks, n = 92), mid–late fetal life (≥17 weeks, n = 67), or unexposed controls (n = 143). Of the 92 girls initially exposed in early fetal life, a subgroup was exposed exclusively in early fetal life (n = 22). In an independent confirmatory cohort, 1210 girls were followed from infancy to adolescence. Their exposure was maternal self-reported (any) use of paracetamol during pregnancy and reported early in the third trimester (yes/no). MAIN RESULTS AND ROLE OF CHANCE Early fetal exposure was associated with reduced ovarian volume (−0.11 cm3, 95% CI −0.19 to −0.03) and reduced uterine volume (−0.18 cm3, −0.35 to −0.01), whereas mid–late fetal exposure was associated with fewer ovarian follicles (−1.05 follicles, −1.71 to −0.39) compared to unexposed girls. AMH levels were lower in girls exposed exclusively in early fetal life (−0.45 SDS, −0.87 to −0.03) compared to unexposed girls. Maternal urinary paracetamol concentrations were inversely associated with ovarian and uterine volume as well as breast tissue diameter. In the independent confirmatory cohort, fetal paracetamol exposure was associated with reduced uterine volume at puberty (−4.11 cm3, −7.29 to −0.92) and smaller ovarian volume during adolescence (−2.76 cm3, −4.82 to −0.70). LIMITATIONS, REASON FOR CAUTION The observational design of the study allows evaluation of exposure outcome associations, while the causality interpretation is supported by consistency with experimental models demonstrating comparable effects. Residual confounding by indication for paracetamol use cannot be completely excluded, although the results were robust after accounting for fever and other maternal factors. The analytic design of the current study limited our ability to evaluate whether frequency or patterns of paracetamol use influenced the observed associations. WIDER IMPLICATIONS OF THE FINDINGS In this prospective cohort study of infant girls, prenatal exposure to paracetamol was associated with differences in several markers of ovarian development, including ovarian volume, follicle number, and circulating AMH, as well as uterine volume and breast tissue diameter. The associations with reduced ovarian and uterine size were also observed in a confirmatory cohort followed to adolescence. Whether these early-life differences have long-term clinical relevance, including effects on reproductive lifespan, remains uncertain and requires analyses in studies with extended follow-up. FUNDING This research was supported by Rigshospitalets Research Council under grant (E-22717-21), 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 Foundation (2020-0385), and The Danish Centre for Endocrine Disrupting Substances (CeHoS) (2022-23219). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. 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 All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. One author (MA) is a government official.
Article Publication Date: 08/09/2026
DOI: 10.1093/hropen/hoag073
