September 9, 2026

expert reaction to study on paracetamol in pregnancy and ovarian development / uterine volume in daughters

Scientists comment on a study in Human Reproduction Open on paracetamol in pregnancy and ovarian development / uterine volume in daughters

Prof Dimitrios Siassakos, Professor in Obstetrics and Gynaecology, University College London, said:

“This was not a randomised controlled trial, and there is likely some confounding not accounted for.

“They only adjusted for confounding by indication for fever, and not for other conditions, particularly autoimmune, that may cause pain and can also affect ovarian development.

“The clinical significance of the findings, even if they were true, is uncertain. When one looks at Table 3, after all the adjustments the only statistically significant findings, contrary to the ‘headlines’ in the abstract (anti-Mullerian hormone was NOT different after adjustment) is a small difference in ovarian volume with early exposure, which ONLY appeared with modelling (look at Table 2 in comparison) and a modest difference in sum of follicles with late exposure.

“But the authors have performed so many comparisons, that they fell in the trap of multiple statistical testing – if you test 20 associations one will be found ‘significant’ at p.05 level by chance alone, if you test 40 associations / outcomes you will find two associations ‘significant’ at p.05 level by chance alone.

“In summary, after adjustment only one association persisted and one appeared, and these two have far too high likelihood of being due to chance or due to residual confounding by indication, despite their best efforts. This paper would not change my practice or advice.”

Dr Adam Brentnall, Reader in Biostatistics at Queen Mary University of London, said:

“All medical treatments involve weighing potential benefits against potential harms. This study addresses an important question about whether paracetamol use during pregnancy might affect the reproductive development of female infants. The investigators used a prospective study design, recruiting pregnant women before outcomes were known and then examining associations between maternal paracetamol use and measures of ovarian development in their children.

“While the study provides valuable data and raises questions that deserve further investigation, I do not believe the strength of the conclusions presented in the paper, press release and accompanying commentary is fully supported by the statistical evidence. That is, it remains unclear whether use of paracetamol at the levels taken by study participants really does significantly alter ovarian function of female infants.

“There are at least three reasons for caution.

“The researchers carried out a large number of statistical comparisons, increasing the likelihood that some apparently positive findings could occur by chance alone. The published analyses do not appear to adequately address this issue.

“The analyses reported in the paper differ in important ways from the study plan that was registered in advance. Pre-registration is intended to reduce the risk of selective reporting. When analyses diverge from the original plan, there is a greater possibility that attention is focused on the most striking results rather than those initially specified.

“Aspects of the statistical methodology, together with potential concerns about participant selection and missing data, create additional uncertainty around the findings.

“In conclusion, the findings need to be interpreted with considerably more caution than suggested by the press release.”

Dr Gavin Stewart, Statistical methods editor at the Campbell Collaboration, and Senior Lecturer in Evidence Synthesis at Newcastle University, said:

“This study requires extremely cautious interpretation.  The study design means it’s impossible to make any causal claims.  The small sample size and large numbers of outcomes make false positive findings very difficult to distinguish from any potential true effect.  We cannot conclude from this study that paracetamol is causing these effects.

“When you hunt really hard for a pattern you inevitably find one.  I am worried that the authors are over-interpreting the one they found.  They set six primary outcomes – that gives you a 25% chance of false positives right off the bat.  And it gets worse with secondary outcomes without even considering causation, biological plausibility, effect magnitude or the heterogeneity of individual responses.

“I am very concerned that this exploratory study will be misinterpreted.  Pregnant women already have a limited choice of pain medication, and paracetamol has an extremely high safety profile.  They should not conclude from this study that paracetamol will harm their child.”

Prof Franziska Denk, Professor in Neuroscience at King’s College London, said:

“The press release is very responsibly written and at pains to point out (correctly) that this does not yet mean that women should stop taking paracetamol when indicated during pregnancy.

“It is good quality research, although it is important to point out that while 67-140 people per group seems like a lot, it is actually not such a large sample, considering that the authors measured 13 different outcomes. To have total confidence that we are not looking at chance connections, one would probably ideally have wanted more like 250-650 people per group, not 300 people in total.

“The authors argue that it fits well with existing pre-clinical literature, and they see something similar in a replication cohort. One caveat to all this is that when we approach large, complex datasets with expectations in mind, it can be remarkably easy to find individual aspects that support prior work or somehow fit our expectations. These days, more and more scientists therefore try and ‘pre-register’ their analysis plans, i.e. specify ahead of time exactly what they want to do. The authors of the current study did log their trial on a repository, but the log does not contain enough statistical detail to ascertain that they did not accidentally pick up noise.

“In the early life exposure group, there were a lot more smokers than in the other two groups. Smoking has a huge effect on pretty much every health outcome.  This and other confounders are adjusted for in the initial cohort, but it is not clear to what extend confounders were adjusted for in the replication cohort.

“Right now, I think it is too early to recommend a change in behaviour – as correctly indicated by the authors in the press release.  

“Pregnant women should not be worried, as very nicely laid out in the original press release.”

Prof Stephen Burgess, Professor of Biostatistics at the University of Cambridge, said:

“This study has several notable weaknesses.

“Even at face value, the statistical evidence that paracetamol usage is linked to fetal outcomes is weak. The headline result – that paracetamol usage is linked to reduced ovarian volume – only just achieves the minimal conventional threshold to be declared as a scientific finding. As part of this analysis, the authors considered 11 other outcomes – only one other outcome achieved the same threshold. The scientists appear to have tested a lot of different hypotheses, and focus their presentation on the small number of findings that show associations – this is selective reporting. The associations are all based on small sample sizes, and so there is a considerable risk that these are chance findings. There is also a substantial amount of missing data – only two-thirds of girls in this study had measurements of ovarian volume.

“Mothers who took paracetamol during pregnancy are likely to differ substantially from those that did not – this is known as confounding. Confounding makes it difficult to know whether differences between outcomes are attributable to paracetamol itself or to other characteristics of the mothers or their pregnancies.

“Even if these differences are statistically robust and even if they are attributable to paracetamol, this study cannot establish paracetamol as a cause. It may be that these findings are driven by infection or fever – women take paracetamol due to mild sickness, and this sickness is the cause of differences in early-life ovarian volume. It may be that impaired fetal development and its causes are what lead to increased paracetamol usage, not that increased paracetamol usage leads to impaired fetal development.

“Finally, it is not clear whether the relatively small differences in ovarian volume, follicle number, and hormone levels observed in infancy have any meaningful clinical consequences. It is also not clear whether they are sustained into adulthood, or whether they have any effect on fertility or reproductive lifespan.

“Paracetamol has been taken for over 100 years, and so the burden of proof that it is harmful should be high. It is one of the only pain-relieving medications that can be taken during pregnancy. Even if there are negative consequences of taking paracetamol during pregnancy (which this study only provides weak evidence to support), there are also likely future negative consequences attributable to taking away one of the only remaining available and widely-tolerated medications from pregnant women.

“This is a small study which performed many different analyses, the majority of which did not show associations with paracetamol usage. If you perform many analyses, you will observe some associations solely due to chance alone. But even if we accept the associations as meaningful, they fall short of showing that paracetamol has a harmful effect: paracetamol usage may be an indicator of impaired fetal development, rather than its cause.”

‘Fetal exposure to paracetamol is associated with altered markers of ovarian development and reduced uterine volume in girls: the COPANA study’ by Margit B. Fischer et al. will be published in Human Reproduction Open at 00.05 UK time on Wednesday 9 September, which is when the embargo will lift.

DOI: https://doi.org/10.1093/hropen/hoag073

Declared interests

Stephen Burgess: “I have no relevant conflict of interest to declare.”

Gavin Stewart: “No conflicts of interest to declare”

Franziska Denk: “None in relation to this work.”

Adam Brentnall: “None”

Dimitrios Siassakos: “None”

For all other experts, no reply to our request for DOIs was received.