The findings, published in Human Reproduction Open, suggest that exposure to acetaminophen, marketed as Tylenol in the United States, may influence reproductive development before birth. Researchers emphasised that the observational evidence does not establish causation or demonstrate that affected girls will experience fertility problems.
Scientists at Copenhagen University Hospital examined 302 infant girls whose mothers participated in the Copenhagen Analgesic Study. Maternal medication use was recorded throughout pregnancy, while urine samples provided additional measurements of paracetamol exposure.
Girls exposed during early pregnancy had ovarian volumes approximately 40% smaller than those of unexposed infants, alongside reduced uterine measurements. Exposure beginning later in pregnancy was associated with approximately 23% fewer ovarian follicles, structures containing immature eggs.
Researchers also identified differences in anti-Müllerian hormone, a biological marker associated with ovarian follicle development. Lower concentrations were observed among girls exposed exclusively during early fetal development, although the clinical significance of these measurements remains uncertain.
The investigation distinguished exposure before 17 weeks of pregnancy from exposure beginning at or after that point. This distinction was intended to examine whether different stages of fetal reproductive development showed particular sensitivity to medication exposure.
Among the 302 infants, 92 had initially been exposed before 17 weeks, while 67 were first exposed later. Another 143 formed the unexposed comparison group.
A separate cohort involving 1,210 girls provided additional evidence extending beyond infancy. Researchers identified associations between prenatal exposure and smaller uterine volumes at puberty, together with reduced ovarian volumes during adolescence.
However, the confirmatory cohort included exposure to paracetamol or other non-steroidal anti-inflammatory medicines, complicating interpretation of the findings. Not every reproductive measurement showed consistent differences across the two populations.
Lead researcher Margit Bistrup Fischer and colleagues cautioned that the observed anatomical differences cannot establish whether reproductive capacity or the timing of menopause will eventually be affected.
The study also found associations between higher maternal urinary paracetamol concentrations and smaller ovarian and uterine volumes. Measurements of breast tissue, another indicator of hormonal activity during infancy, showed corresponding differences.
Researchers adjusted their analyses for several potential influences, including maternal body mass index, smoking, alcohol consumption, fertility treatment and other medication use. Associations persisted after accounting for maternal fever, although unmeasured influences could not be excluded.
The findings are consistent with experimental investigations showing that prenatal paracetamol exposure can affect ovarian follicle formation in animals. Nevertheless, scientists cautioned against directly translating laboratory findings into predictions about human fertility.
The European Society of Human Reproduction and Embryology highlighted the importance of longer follow-up studies to determine whether developmental differences persist and produce measurable reproductive consequences during adulthood.
Medical guidance continues to recognise paracetamol as an option for treating pain and fever during pregnancy when clinically necessary. Researchers stressed that pregnant women should not interpret the findings as grounds for abandoning appropriate treatment.
Untreated fever and significant pain can themselves create health concerns during pregnancy. Decisions about medication therefore require consideration of both potential exposure risks and the consequences of leaving symptoms untreated.
The study did not establish a threshold below which exposure carries no developmental association. Its design also prevented reliable conclusions about whether particular dosing schedules or frequencies produced different outcomes.
An accompanying editorial by Christian De Geyter of the University of Basel examined the significance of connecting prenatal medication exposure with reproductive development after birth. The investigation provides human evidence for associations previously explored largely through experimental models.
The research population was restricted to healthy singleton pregnancies involving women of European ancestry, limiting the extent to which the results can be generalised across broader populations.
Investigators additionally acknowledged difficulties measuring very small infant ovaries using ultrasound, which reduced the number of complete observations available for certain reproductive indicators.
The Copenhagen study enrolled pregnant women between March 2020 and November 2022. Participants completed medication questionnaires at fortnightly intervals, allowing researchers to distinguish reported exposure during different stages of pregnancy.
Maternal urine samples were analysed using laboratory techniques capable of detecting paracetamol concentrations. These measurements supplemented self-reported medication histories and provided an independent indicator of exposure during pregnancy.
The median cumulative paracetamol dose reported by mothers was three grams, with substantial variation between participants. Researchers examined these exposure measurements alongside ultrasound assessments and circulating reproductive hormone concentrations in the infants.
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