At three months of life the differences were already visible on the ultrasound. In girls exposed to paracetamol during pregnancy, a team of Danish researchers observed smaller ovaries and uterus, fewer ovarian follicles, and changes in some reproductive hormones. And the signal did not remain confined to the first months: results in the same direction also appeared in a second cohort of girls followed until adolescence.
The study, published in the scientific journal Human Reproduction Opencomes from the Copenhagen University Hospital – Rigshospitalet and brings attention to a hitherto much less studied aspect of prenatal exposure to paracetamol: the development of the female reproductive system. Before the definitive publication, the work had also been released as a preprint.
The differences appear as early as three months
The main work is the Copenhagen Analgesic Study, COPANA, a prospective cohort conducted in Denmark between 2020 and 2022. The researchers enrolled 685 women in the first trimester of pregnancy and subsequently examined 302 daughters, on average around three months of age.
It’s a particular window. In the first months after birth the reproductive hormonal axis is temporarily reactivated in the so-called minipuberty: ovaries, uterus and hormones thus become observable at a time when they are going through an intense phase of development. Detailed data on ovarian and uterine morphology and reproductive hormones had already been collected on the 302 girls in the COPANA cohort.
During pregnancy, mothers reported any paracetamol intake every two weeks. For 299 women, the researchers also had first-trimester urine samples, which they used to directly measure the presence of the drug.
The girls were then divided based on the time of exposure. Among those exposed before the 17th week of pregnancy, the ovarian volume was on average 0.11 cubic centimeters smaller and the uterine volume 0.16 cubic centimeters smaller than in unexposed girls. Exposure from the 17th week onwards was associated with approximately one fewer ovarian follicle.
Follicles are the structures in the ovary that contain immature eggs. And this detail is of particular interest to researchers because experimental studies conducted previously on animals had already indicated the possibility that fetal exposure to paracetamol interfered with the formation of primordial follicles. The new work therefore searches for similar signals directly in humans for the first time.
Paracetamol measured in urine and the signal on hormones
The result did not emerge only from the questionnaires filled out by the mothers. Higher concentrations of acetaminophen measured in urine during the first trimester were also associated with smaller size of ovaries, uterus and breast tissue, all tissues sensitive to sex hormones.
In a smaller subgroup of girls exposed exclusively in the early part of pregnancy, the researchers also observed lower levels of anti-Müllerian hormone, AMH, produced by ovarian follicles and used as one of the markers of ovarian activity.
They are different pieces of the same photograph: organ size, number of follicles, hormones. Taken together, they led the authors to hypothesize that fetal exposure to paracetamol may be associated with changes in ovarian development and female reproductive tissues.
The same signal reappears until adolescence
The Danish group then looked for confirmation in a different population: 1,210 girls belonging to a second cohort from Copenhagen, followed from childhood to adolescence.
Here too, the daughters of women who reported taking acetaminophen during pregnancy showed differences in the size of their reproductive organs. Uterine volume was smaller during puberty and ovarian volume in adolescence.
It is probably the most interesting step of the study, because it moves the signal beyond the photograph taken at three months. The two cohorts are different and the exposure was also reconstructed differently, but the association reappears at later ages.
From here to adult fertility, however, there is still a portion of life that the study did not follow. The researchers did not measure pregnancies, ability to conceive or age at menopause, so we don’t know if these anatomical and hormonal differences will have concrete reproductive consequences. It is the passage that the next follow-ups will have to face.
A drug used for decades, now under a different lens
Paracetamol remains one of the most used analgesics and antipyretics during pregnancy. Precisely for this reason, a possible effect on reproductive development deserves attention even when the differences observed are small.
The study is observational, so it can identify associations without establishing on its own that the drug caused them. Fever, pain, infections and the other reasons that led women to take paracetamol can indeed enter into the equation. The authors tried to take various factors into account and strengthened the analysis by combining urine measurements alongside the questionnaires, but other studies and above all longer follow-up will be needed.
The indications on the use of the drug, meanwhile, remain those already in force. AIFA and the European Medicines Agency indicate paracetamol as usable during pregnancy when clinically necessary, recommending the lowest effective dose for the shortest time necessary.
However, the new study adds a piece that was missing until now: it doesn’t just look at birth or neurological development, it looks at the ovaries, follicles and uterus of daughters. And those differences, at least in the two Danish cohorts, are consistent enough to be worth following as girls become women.
