Paracetamol use during pregnancy has been linked to changed reproductive development in daughters.
According to a press statement from Oxford University Press this week, researchers in Denmark have found that girls whose mothers took paracetamol during pregnancy had smaller ovaries, fewer ovarian follicles (the structures that contain immature eggs), smaller uteruses and lower levels of reproductive hormones at three months old.
The study was published on Wednesday in Human Reproduction Open, one of the world’s leading reproductive medicine journals, with researchers saying their results were consistent with findings from several previous studies in animals.
However, they noted that, as this was an observational study, the findings do not establish a direct cause-and-effect relationship.
They said women should not be alarmed by their findings, which required confirmation in “further, longer-term investigations and follow-up”.
A few academics from Oceania have raised the fact that the results were not strong and convincing enough.
Professor Gavin Pereira, School of Population Health at Curtin University, Perth, Western Australia said despite the research results current Australian advice remained in place.
“That is, paracetamol can be used as directed for pain or fever during pregnancy, and this study alone should not prompt anyone to stop medically indicated use,” Professor Pereira said.
“Residual confounding by indication is plausible and, in my opinion, likely. It is one of the major barriers to causal interpretation for this study. Although the authors examined fever specifically, the analyses do not adequately rule out confounding by the broader conditions for which paracetamol was taken, such as headache, pain or infection, which may themselves be associated with fetal development.”
He it would be interesting to know whether “it’s the paracetamol or the reason it was taken”.
Professor Beverley Lawton, Director of the Centre for Women’s Health Research at the Faculty of Health, Victoria University of Wellington said it was very hard to make overall statements from these cohort studies.
“The evidence is not strong that paracetamol has a lasting affect on the baby. The worry is the reason for taking the paracetamol – fever can be causing the harm and we know fever is not good for the baby.
“The advice is to only take medications in pregnancy if you need to. Not treating the fever is potentially harmful for the pregnancy – ask a doctor or midwife for advice.”
Professor Andrew Shelling, Department of Obstetrics, Gynaecology and Reproductive Sciences, University of Auckland said the findings warranted attention, as the potential implications were significant.
“There are previous animal studies that provide some support for the associations reported in this epidemiological study. The research appears to have been conducted rigorously by an experienced group with expertise in this field and has been published in a reputable, peer-reviewed journal.
“However, this single study should not be regarded as definitive evidence of an association. Rather, it highlights the need for further research to investigate these findings and determine whether they can be replicated in other populations and settings.
He said the study also underscored the value of longitudinal human research, which could provide a depth of information that was difficult to achieve through retrospective studies. The biological changes observed appeared to be meaningful and may have implications for female reproductive health later in life, he said.
Associate Professor Gergely Toldi of Liggins Insitute, University of Auckland and consultant neonatologist, Starship Children’s Health said paracetamol was currently regarded as the safest pain medication during pregnancy.
However, guidelines recommend using the lowest effective dose for the shortest possible duration and avoiding regular or prolonged use.
“This thorough, well-designed study, conducted in Denmark, reinforces the importance of minimising paracetamol intake during pregnancy, particularly before 17 weeks of gestation, suggesting that paracetamol might have previously less appreciated negative effects on the developing reproductive organs of female fetuses.”
“Whether this also translates to a reproductive disadvantage or reduced fertility in exposed infants is yet to be determined in future studies. However, the findings will likely prompt a more cautious use of paracetamol during pregnancy than before.”
He said women needed to consult their doctors or midwives for the best medication options available to them.
“Our concern is less about the statistical methodology and more about the risk that findings such as these are interpreted beyond what the data actually show,” said Dr Lakshmi Ravikanti, President of the New Zealand Gynaecology Society
“The study reports associations between prenatal paracetamol exposure and a number of surrogate markers of ovarian and uterine development in infancy. Some of the reported differences reach statistical significance, but the absolute effect sizes are very small, the outcomes are indirect measures rather than clinical endpoints, and the study remains observational, leaving considerable scope for residual confounding.
Dr Ravikanti said, most importantly, there was currently no evidence that paracetamol exposure in pregnancy impaired the future fertility of female offspring.
She said the study did not assess fertility, fecundity, time to pregnancy, IVF outcomes, age at menopause, or any other clinically meaningful reproductive endpoint yet it identified associations with infant and adolescent anatomical and hormonal measurements whose long-term significance remained uncertain.
“I think there is a real risk that studies such as this generate unnecessary anxiety among pregnant women. Paracetamol remains one of the most widely used medications in pregnancy, and many women reading headlines about this work may conclude that taking paracetamol could compromise their daughter’s fertility. That is simply not a conclusion supported by the available evidence,” Dr Ravikanti said
“For me, this is an interesting hypothesis-generating study that warrants further investigation and long-term follow-up. It is not a practice-changing paper, nor does it provide evidence that occasional or clinically indicated paracetamol use during pregnancy causes infertility in female offspring.”
A woman’s reproductive function and lifespan is established during her foetal life in the womb. Girls are born with all the immature egg follicles they will ever have and these gradually deplete throughout life until the menopause.
Paracetamol is the most commonly-used medication in pregnancy but, until now, it was unknown whether foetal exposure to the drug might affect the development of the ovarian egg reserve and later reproductive function in girls and women in the same way that had been observed in animal studies.
To investigate this, researchers established a prospective observational study called the Copenhagen Analgesic Study (COPANA) at the Copenhagen University Hospital–Rigshospitalet that ran from March 2020 to November 2022. As far as they are aware, this is the first prospective study to evaluate the associations between foetal exposure to paracetamol and postnatal ovarian function.
A total of 3,425 healthy pregnant women were invited to participate and, of these, 685 women were enrolled during the first trimester of pregnancy and 302 baby daughters were examined when they were three months old.
The mothers reported paracetamol use every two weeks and provided urinary samples in the first trimester, which the researchers analysed for paracetamol levels. The girls were classified by the timing of their initial exposure to paracetamol: during early foetal life at less than 17 weeks (92 babies) and mid-late foetal life at 17 weeks or more (67). They were compared to a control group of babies who had not been exposed to paracetamol (143).
The researchers also looked at a separate group of 1,210 girls from the Copenhagen Mother-Child Cohort, who were followed from infancy to adolescence and whose mothers, during the third trimester, had reported any paracetamol use during pregnancy. This cohort started in 1996 and included pregnant women from three university hospitals in Copenhagen.
