Girls whose mothers took paracetamol (acetaminophen) during pregnancy had smaller ovaries at three months old, on average, than those whose mothers didnāt take the drug, according to a study of about 300 infant girls in Denmark. Infant boys whose mothers took paracetamol had smaller testes on average too, the study found.
That doesnāt prove paracetamol caused the reduction in the average size of ovaries and testes, though ā this association could be a result of the conditions that led to the women taking paracetamol during pregnancy, or even due to chance alone. Nor is it clear whether having smaller ovaries or testes as an infant affects fertility in adulthood. However, the findings are in line with separate studies done in rats and mice, in isolated human ovaries and in human embryonic cells.
āWe still recommend that pregnant women should use paracetamol with high fever or strong pain,ā says at Copenhagen University HospitalāRigshospitalet. Not doing so can be risky, she says.
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But most of the women in the study used paracetamol for headaches or musculoskeletal pain, rather than fevers, and could have managed their pain or discomfort in other ways, such as via rest, heat treatment or physiotherapy, says Fischer.
āWe should have a dialogue about when paracetamol is actually necessary,ā she says. āIt is still a drug and it does have side effects. Maybe it shouldnāt be the first thing that we grab when we have discomfort.ā
The issue is that there are almost no safe drug-based alternatives to paracetamol for pregnant women. Most other painkillers arenāt recommended because they can cause congenital conditions.
Fischerās team recruited 685 pregnant women during their first trimester, who were asked about their use of medicines every two weeks. They had an fetal ultrasound during their third trimester, and 302 daughters were examined around three months after birth.
Those exposed to paracetamol as a fetus had, on average, 40 per cent smaller ovaries by volume, 13 per cent smaller uteruses by volume and 23 per cent fewer ovarian follicles ā the sacs that nurture immature eggs ā compared with those who werenāt exposed. Higher doses were associated with a bigger effect, says Fischer, but no women took more than the recommended daily maximum of 4000 milligrams.
The researchers also analysed data from another study on 1210 girls born in Copenhagen between 1997 and 2002, and found a link between fetal exposure to paracetamol and smaller ovaries during adolescence.
In animal studies, such effects led to reduced fertility and earlier reproductive ageing, but it isnāt clear whether this applies to people. āWe cannot say anything about the reproductive consequences for these girls,ā says Fischer. That will require long-term follow-up, which is hard to do.
The team also examined the boys who were born to the 685 women. āWe do see a difference, on average, in the boys as well,ā says Fischer. ā[They] have a reduced testicular volume.ā
Animal studies suggest this could affect fertility in adulthood, but again it is still unclear if this will be the case for the boys. āWe canāt say anything about that because our cohort does not follow them that long,ā she says.
A paper describing the findings in girls was published today. A separate paper describing the findings in boys has been accepted by the same journal, but not yet published, says Fischer.
āIt is still too early to sound the alarm, and to remove this tool from the therapeutic arsenal for treating pain and fever,ā says at the National Institute of Health and Medical Research in France, who, in 2022, co-authored research showing that .
But this latest study, along with one from last year showing that paracetamol , suggest that the precautionary principle should be applied, especially during the first trimester, says Mazaud-Guittot.
āRaising awareness of alternative, non-pharmacological methods should help to encourage a reduction in the use of medication for the treatment of various mild pains,ā she says.
āThis paper would not change my practice or advice,ā says at University College London. The team carried out a number of different statical analyses, he says, and the more of these you do, the greater the odds of getting a statistically significant association by chance.
āI do agree that we cannot exclude the possibility of chance findings,ā says Fischer. ā[But] adjusting for multiple testing could mean that we fail to detect a real effect.ā
Another issue is that people taking these medications could be sicker, including with one of the many infections that affect fetal development. They might also eat and behave differently, or vary genetically, says at the University of Pennsylvania. The team tried to take account of such confounding factors, but couldnāt completely rule them out.
āI would not jump to the conclusion that the statistical association observed is a causal association,ā says Lee. He thinks there should be further studies into this, but establishing a causal link, if there is one, wonāt be easy. A trial in which women were randomly assigned to take paracetamol or not would be the best way, but this would be unethical in pregnant women, says Fischer.
There have been claims that taking paracetamol during pregnancy increases the risk of autism, but the evidence suggests otherwise. āThis in no way changes the conclusion that paracetamol is not linked to autism, as multiple studies featuring millions of pregnancies across Sweden, Denmark, Norway, Hong Kong, Taiwan and Japan have shown,ā says Lee.
Human Reproduction Open
