Prenatal paracetamol linked to smaller ovaries and altered hormone markers in infant girls

Girls whose mothers took paracetamol during pregnancy had, on average, a 40 percent smaller ovarian volume, a 13 percent smaller uterine volume and 23 percent fewer ovarian follicles when examined at three months of age, according to a prospective observational study conducted in Denmark and published in the journal Human Reproduction Open. The girls exposed to the drug in early fetal life, before 17 weeks of gestation, also showed lower levels of anti-Müllerian hormone, an established marker of the ovarian egg reserve. The findings, reported by researchers at Copenhagen University Hospital–Rigshospitalet, are consistent with results from several previous animal studies, but the investigators stress that an observational design cannot establish a direct cause-and-effect relationship between the medication and the developmental differences they measured.

The study, known as the Copenhagen Analgesic Study, or COPANA, ran from March 2020 to November 2022 and is, as far as its authors are aware, the first prospective investigation to evaluate the associations between fetal exposure to paracetamol and postnatal ovarian function in humans. The question matters because a woman’s reproductive function and reproductive lifespan are established during fetal life. Girls are born with all the immature egg follicles they will ever possess, and this reserve gradually depletes throughout life until the menopause. Paracetamol, also known as acetaminophen, is the most commonly used medication in pregnancy, yet until now it was unknown whether fetal exposure to the drug might affect the development of the ovarian egg reserve and later reproductive function in the way that animal experiments had suggested.

To address the question, the researchers invited 3,425 healthy pregnant women to participate and enrolled 685 of them during the first trimester of pregnancy. In total, 302 baby daughters were examined when they were three months old. The mothers reported any paracetamol use every two weeks and provided urinary samples in the first trimester, which the researchers analysed for paracetamol levels. The girls were classified according to the timing of their initial exposure: 92 babies had been exposed during early fetal life at less than 17 weeks of gestation, and 67 had been exposed in mid-to-late fetal life at 17 weeks or more. They were compared with a control group of 143 babies who had not been exposed to paracetamol at all.

Dr Margit Bistrup Fischer, a post-doctoral researcher in the Department of Growth and Reproduction at Rigshospitalet who led the COPANA study, described the measurements in detail. “When the babies were three months old, we found that those who had been exposed to paracetamol during fetal life had, on average, a 40% smaller ovarian volume, a 13% smaller uterine volume and 23% fewer ovarian follicles,” she said. “The girls who had been exposed to paracetamol in early fetal life had lower levels of Anti-Müllerian hormone, which is an established marker of ovarian egg reserve.”

The results did not stand alone. The researchers also examined a separate group of 1,210 girls from the Copenhagen Mother-Child Cohort, a study that began in 1996 and included pregnant women recruited at three university hospitals in Copenhagen. In this confirmatory group, the mothers had reported any paracetamol use during pregnancy during the third trimester, and the daughters were followed from infancy into adolescence. In these girls, fetal exposure to paracetamol was associated with smaller uteruses at puberty and smaller ovaries during adolescence, a pattern that mirrors the infant findings and extends them across a much longer developmental window.

Dr Fischer was careful to frame what the study does and does not show. “Animal studies have demonstrated that impaired formation of ovarian follicles can lead to reduced fertility and earlier reproductive ageing,” she said. “Whether the differences observed in our study have implications for fertility and age at menopause in humans remains unknown and will require long-term follow-up of the girls in our cohort.” She added that women who have used paracetamol during pregnancy should not be alarmed by the findings, because the study examined associations at the population level and cannot predict outcomes for any individual woman or child. Many women who used paracetamol during pregnancy had daughters whose ovarian measurements were similar to those of daughters born to women who did not use the drug.

The researchers also emphasised the limits of what the data can support. “Importantly, our study does not evaluate if paracetamol causes reproductive problems, nor does it provide evidence that prenatal exposure affects future fertility or age at menopause,” Dr Fischer said. “Although we observed similar associations in an independent cohort, long-term follow-up is needed to determine whether these early-life differences have any clinical significance later in life.” This distinction between statistical association and causal effect is a central feature of observational research, and the investigators noted that their findings required confirmation in further, longer-term investigations and follow-up.

The team noted that the mothers in the study took relatively low levels of paracetamol and that none exceeded the recommended daily maximum dose of 4,000 milligrams. Most took the medication for headaches or musculoskeletal pain rather than for severe illness. “In some of these situations, non-pharmacological approaches, such as rest, hydration, physiotherapy, exercise, heat treatment, or other supportive measures, may be sufficient if women receive appropriate counselling,” Dr Fischer said. She stressed that decisions about pain management during pregnancy should always be individualised and made in consultation with a healthcare professional, and that the findings should not discourage women from using paracetamol when it is medically indicated. Current guidelines in Europe and the United Kingdom continue to recommend paracetamol as the first-choice medication for treating pain and fever during pregnancy when clinically needed, because untreated conditions such as high fever or severe pain can themselves pose risks to both the mother and the developing fetus.

In an accompanying commentary in the same journal, Professor Christian De Geyter, who leads the department of Reproductive Medicine and Gynecological Endocrinology at the University Hospital of Basel in Switzerland, argued that the findings carry considerable weight for the field. “The eminent importance of Fischer et al’s (2026) findings cannot be stressed enough!” he wrote. He noted that both the duration of intake and the applied dosage must be taken into consideration, a common principle in toxicology, but that the observed dose-responsiveness of the findings points towards a distinctive effect and fits well with the already published animal research data. “Recommendations on the use of paracetamol during pregnancy must now be revised,” he wrote, while emphasising that follow-up of the exposed girls should extend into adulthood and up to menopause. “The attention this study is likely to generate among both professionals and the general public will hopefully encourage sustained long-term follow-up of the exposed individuals,” he concluded.

The study, titled “Fetal exposure to paracetamol is associated with altered markers of ovarian development and reduced uterine volume in girls: the COPANA study”, was published in Human Reproduction Open with the DOI 10.1093/hropen/hoag073, alongside the commentary by Professor De Geyter under DOI 10.1093/hropen/hoag074. For now, the measured differences in ovarian volume, follicle number, uterine volume and anti-Müllerian hormone levels remain associations observed in a well-characterised prospective cohort and an independent confirmatory group, not evidence of harm to future fertility. The decisive question, whether the smaller follicle counts and organ volumes seen in infancy and adolescence translate into reduced fertility or earlier menopause in adulthood, will only be answered by following the enrolled girls over the coming decades, an effort that both the study team and the commentary author say is now essential.

Subject of Research: Paracetamol use during pregnancy is linked to changed reproductive development in daughters

Article Title: Paracetamol use during pregnancy is linked to changed reproductive development in daughters

Article References: Paracetamol use during pregnancy is linked to changed reproductive development in daughters. Original publication (Bibliographic details unavailable.)

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Keywords: Paracetamol, during, pregnancy, linked, changed, reproductive, development, daughters, scientific research