June 22, 2017

expert reaction to study investigating the effect of paracetamol on the brains of unborn mice

Publishing in Reproduction researchers examine mouse brain structure and behaviour following prenatal exposure to paracetamol.

Prof. Ieuan Hughes, Emeritus Professor of Paediatrics University of Cambridge, said:

“The study is well designed and undertaken by a group with a lot of experience investigating the effects of chemicals on the developing reproductive tract. The results are convincing in terms of structural changes in regions of the brain that are sexually dimorphic, with also changes in male pattern behaviour in exposed animals.

“Now of course, these data are obtained from studies in mice and are the results sufficient to extrapolate to the human? The authors have not convinced me that their calculations of paracetamol exposure in this study where effects are seen (and only at the 150mg/kg/day not the 50mg/kg/day dose) are akin to what a pregnant women would be exposed to taking paracetamol. Furthermore, in the animal study exposure to paracetamol was daily from 7 days post-coitum to birth. Pregnant women generally take analgesics like paracetamol intermittently for symptoms and generally for a very short period.

“While the study provides interesting data and adds to the body of evidence that analgesics like paracetamol can affect the reproductive tract (and now brain) in rodents, it is my view that there is not sufficient evidence in humans to deter pregnant women taking the occasional paracetamol for symptomatic reasons.”

Dr Rod Mitchell, Research Group Leader, MRC Centre for Reproductive Health, University of Edinburgh, & member of the Society for Endocrinology, said:

“Testosterone is required for masculinisation of the human brain during foetal life and this results in normal sex-specific behaviour in adulthood. This well conducted mouse study shows that some aspects of sexual behaviour in male mice are affected after prolonged exposure to paracetamol (acetaminophen) during pregnancy, with changes in specific areas of the brain linked to masculinisation. This may be due to hormone changes during development, but these were not measured.

“The challenge comes in trying to relate the findings of this study to the situation in human pregnancy. This includes taking consideration of the dose, timing and duration of exposure. The study involved daily exposure to paracetamol for the final two thirds of pregnancy. Brain masculinisation in the human male foetus probably results from testosterone exposure over a period of several weeks during the second half of pregnancy, so prolonged duration of exposure to paracetamol over this period, similar to that described in this mouse study, does not represent how pregnant women generally take paracetamol, which is typically for a short duration (24-48h). It has been shown that prolonged paracetamol exposure for 7 days can reduce testosterone production by the human foetal testis, whereas, short-term exposure (24 hours) does not. The timing of exposure may also be important as it has been shown that in rodents there are specific ‘windows of sensitivity’ during which testosterone may programme male reproductive development. Whether similar ‘windows of sensitivity’ for brain masculinisation in rodents exist and how they may relate to humans is not clear. The paracetamol doses used in the study are considered relevant to those to which humans are exposed, although differences in drug metabolism between rodents and human can make direct comparison of dosage difficult.

“The findings of this mouse study raise the possibility that prolonged exposure to paracetamol might affect masculinisation of the brain. Studies to directly address the relevance of these findings to humans are still required, although of course very challenging to perform.  It is important to recognise that management of pain and fever during pregnancy are important for the health of mother and baby. This new study therefore reinforces the current recommendation from the Department of Health that pregnant women should only use paracetamol for the minimum period necessary to provide symptomatic relief of pain and fever.”

Dr Ali Abbara, Academic Clinical Lecturer in Endocrinology, Imperial College London, & member of the Society of Endocrinology, said:

“Paracetamol is a widely prescribed pain killer and is generally regarded as being a very safe option. Due to greater concern for adverse effects being associated with the use of other classes of pain-killers, paracetamol is often recommended during pregnancy. This interesting study suggests that paracetamol use may have some subtle effects on the development of the brain and behaviour of male mice. Extrapolating the doses used across species to humans, the study used similar doses to those used in pregnant women, however these were administered for a prolonged duration during the pregnancy. Paracetamol is usually used infrequently at the time of pain in pregnant women, and it is not known whether the more usual infrequent use of paracetamol at times of pain in pregnancy would lead to any adverse effects. However, it would certainly be useful to have more studies assessing the safety of paracetamol use during human pregnancy. A useful principle is to use as few medications that are not essential for health for as short a duration of time as is possible during pregnancy.”

Dr Channa Jayasena, Clinical Senior Lecturer and Consultant in Reproductive Endocrinology, Imperial College London and Hammersmith Hospital, & member of the Society for Endocrinology, said:

“Mice are over 1000 times lighter than humans, so it is tricky to compare doses between the species. When the paracetamol dose was corrected for body weight, no bad effects were seen in mice; only excessive paracetamol doses caused problems. We should always be vigilant to the safety of drugs, but we need more much evidence before saying paracetamol is unsafe.”

* ‘Prenatal exposures to paracetamol/acetaminophen and precursor aniline impair masculinisation of male brain and behaviour’ by Hay-Schmidt et al.   published in Reproduction on Thursday 22 June.

Declared interests

Prof. Ieuan Hughes: No conflicts of interest.

Dr Rod Mitchell: “I have no conflicts of interest to declare other than the fact that my research focuses on a similar area.”

Dr Ali Abbara: No conflicts of interest.

Dr Channa Jayasena: No conflicts of interest.