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A new study, published in Endocrine Connections, examines the association between taking paracetamol during pregnancy and future fertility of offspring in mice and rats.
Prof. Joyce Harper, Professor in Human Genetics and Embryology, Institute for Women’s Health, UCL, said:
“Guidance on what pregnant women should eat and drink and what drugs they can safely take continuously changes as new scientific data is obtained. A huge limitation is that testing exposure during pregnancy in humans is very difficult to do. This study summaries three reports from 2016 done on rats and mice that all show that prenatal paracetamol exposure disrupts female reproductive development. The three main limitations of the rodent studies are the small numbers of animals used, the doses of paracetamol administered and the extrapolation to the humans, but epidemiological studies are urgently needed to gather more data.”
Prof. Ying Cheong, Professor of Reproductive Medicine and Consultant in Reproductive Medicine and Surgery, University of Southampton, said:
“In this review article, Kristensen and colleagues collated the evidence provided by three research papers looking at the impact of mothers taking paracetamol on the fertility of their daughters. Whilst the paper is well written and argued, one cannot make much inference from its conclusion on humans because the studies referred to were based on a small number of mouse and rat experiments, with various important confounders unaccounted for. There is also a lack of a systematic presentation of studies with positive and negative findings, thus the review suffers from significant bias.
“Paracetamol is a useful simple analgesia and this paper should not deter women from taking the drug. It is important that whilst more studies can be conducted to further evaluate the impact of this drug, women should not be ‘scare-mongered’ into not taking paracetamol for simple aches and pains at all!”
Prof. Jean Golding, Emeritus Professor of Paediatric and Perinatal Epidemiology, University of Bristol, said:
“This paper reviews three studies where pregnant mice and rats were given paracetamol. Each study showed an adverse effect on the ovaries of the rodent daughters. The authors speculate that, if similar effects are found in humans, this might have adverse consequences on women’s ability to conceive, particularly as she reaches the late thirties.
“There are obvious caveats. This report is concerned only with three studies; the numbers in each study were small; we don’t know if there were other studies which were not published because the authors found nothing.
“If these findings are robust, it is difficult to know how they relate to human experience as no studies appear to have been published as yet. However there is evidence in both rodents and humans that paracetamol in pregnancy does have an effect on the male reproductive system. It is therefore prudent to continue to remind women to avoid taking non-essential medications during pregnancy.”
Prof Sir Munir Pirmohamed, President-Elect of the British Pharmacological Society, said:
“The authors of this article conclude that paracetamol may be associated with reduced fertility and raise the possibility of premature ovarian failure.
“However, although interesting in terms of findings in animals, one should exercise caution in extrapolating these results to humans for the following reasons.
“Firstly, there are differences between rodents and humans which means that findings in rodents will not necessarily occur in humans.
“Secondly, the doses used in animals were in general much higher than those given in humans. At these doses, it is possible for there to have been damage to other organs such as the liver, which could have produced changes in hormones, which could have harmful effects on female reproductive organs, rather than being a direct effect of paracetamol intake.
“Thirdly, intake of paracetamol in most women, although common, tends to be intermittent rather than regular, and thus the overall dose exposure will be much smaller than that seen in rodent models.
“Finally, although the authors speculate about many different pathways by which paracetamol could affect female fertility, no clear mechanism was identified.
“In conclusion, therefore, this review highlights an association, which is not necessarily causative.
“It is important to note that women may require analgesics in pregnancy because of fever and/or pain, which is important for the health of both the mother and foetus. However, it is always important to avoid taking medicines during pregnancy unless absolutely necessary. Any medicine that is required should be taken for the shortest possible duration at the lowest effective dose. Women who are already taking medicines and become pregnant should not stop taking the medicines without consulting their doctors. If women have concerns about taking medicines during pregnancy, they should discuss with a healthcare professional (nurse, pharmacist or doctor).”
Dr Rod Mitchell, Research Group Leader and Honorary Consultant Paediatric Endocrinologist, MRC Centre for Reproductive Health, University of Edinburgh, said:
“The article is a review of existing literature relating to three separate rodent studies reporting the potential reproductive effects in females exposed to paracetamol during pregnancy.
“Whilst the studies describe effects on the number of developing eggs and on subsequent fertility in rats and mice exposed to paracetamol in-utero, it is important to consider that the findings of these studies cannot be directly applied to humans.
“The authors correctly point to differences in reproductive development between rodents and humans. They also emphasise that the paracetamol exposures used in these studies may not accurately reflect typical human use in terms of dose, timing or duration.
“Importantly, should there be an effect of in-utero paracetamol exposure on the number of eggs of humans, whether it would have a significant impact on fertility is unknown.
“Further research, including laboratory experiments using human tissues or large population-based studies looking at adults exposed to paracetamol in-utero, is required to determine whether paracetamol exposure during pregnancy can adversely affect fertility in humans.
“Current recommendations regarding paracetamol use for the shortest duration necessary to relieve pain during pregnancy should not change on the basis of this review article.”
Dr Sarah Stock, Senior Clinical Lecturer, Honorary Consultant and Subspecialist in Maternal and Fetal Medicine, MRC Centre for Reproductive Health, University of Edinburgh, said:
“This is a review discussing the results of three previously published studies, which suggest that paracetamol taken in pregnancy has potential to reduce fertility in female offspring – however, all the studies were performed in mice or rats, and so the relevance to human pregnancy is not yet clear. In two of the animal studies, the dose of paracetamol used gave a much higher blood concentration of the drug than is found in pregnant women that take the recommended dose of paracetamol. Also, in the animal studies paracetamol was given for a week or more, which is a relatively high proportion of the rodent pregnancy.
“The studies found that female rats or mice whose mothers had been given paracetamol had a reduced number of eggs available for fertilisation. Further research is need to find out whether similar effects are seen in girls and women born to mothers who took paracetamol in pregnancy, and if this has any effect on their fertility.
“Short-term use of paracetamol is currently considered safe in pregnancy, and there is no reason to change this advice or for women to worry. As with all medications in pregnancy, the recommended dose of paracetamol should not be exceeded, and it should only be taken for as long as needed.”
Dr Raj Mathur, Consultant and Clinical Lead for Reproductive Medicine, Manchester NHS Foundation Trust, and Secretary of the British Fertility Society, said:
“This is a review article that does not present new information, but draws attention to three research studies in mice and rats. These studies together suggest that female offspring of mice and rats exposed to paracetamol in early pregnancy have a lower ovarian reserve than offspring who were not so exposed.
“This data is not from humans, and the authors acknowledge that there can be significant differences between species. The dose of paracetamol in one of the studies is very high, well above what would be used in humans. The duration of paracetamol exposure is not clear from the paper – in most cases, pregnant women would use paracetamol for only a short period of time and it is not clear whether these findings would be relevant to their situation.
“Women who are trying to conceive, or who are pregnant, should be careful about the medication they take and discuss any concerns with a doctor. At the present time, all we can say is that continued research and vigilance is required, but women who require pain relief in pregnancy should not be denied this on the basis of this research.”
Dr Sarah Branch, Deputy Director of the MHRA’s Vigilance and Risk Management of Medicines Division, said:
“Women should avoid taking medicines during pregnancy unless absolutely necessary and should speak to their doctor, midwife or pharmacist before doing so. Paracetamol is generally considered to be a safe treatment for pain relief during pregnancy but should be taken at the lowest possible dose for the shortest time.
“The safety of paracetamol, as for all medicines, is carefully monitored. These findings will be carefully evaluated, as with any review, to determine whether they have any implications for the safe use of paracetamol.”
* ‘Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development?’ by Frederic Schrøder Arendrup et al. will be published in Endocrine Connections on Saturday 6 January 2018.
Declared interests
Prof. Joyce Harper: “No conflicts.”
Prof. Jean Golding: “I have no conflicts of interest.”
Prof Sir Munir Pirmohamed: “I am Director of the MRC Centre for Drug Safety Science in Liverpool, and I am also a Commissioner on Human Medicines for the MHRA, and Chair the UK Pharmacovigilance Expert Advisory Group. However, the opinions expressed here are based on my expertise and role with the BPS, and do not reflect the views of any other organisations I am involved with.”
Dr Rod Mitchell: “Dr Mitchell was an author on one of the studies included in the review. Dr Mitchell did not have any involvement in the writing of the review. Dr Mitchell’s research Group is currently conducting research investigating the effects of paracetamol exposure in human tissue.”
Dr Sarah Stock: “I work at the MRC Centre for Reproductive Health, the institution where one of the rodent studies discussed in the review article was performed (Dean et al, 2016), although I had no involvement in the study. No other conflicts of interest.”
Dr Raj Mathur: “I have no conflicts to declare.”
None others received.