EXPERT REACTION: Paracetamol in pregnancy and male sexual development

As a pharmacist, the message that I definitely would not want to be sending out to mums-to-be is to stop taking paracetamol for pain relief because as it stands, it is one of the safest analgesics available on the market for them to use according the Therapeutic Goods Administration (Category A).  As a neuroscientist, there are some limits to how much we can extrapolate the findings of this study.  Firstly, experiments were done in mice.  While mice are routinely used for reproductive and behavioural research, to equate their anatomy and physiology to humans is an oversimplification and neglects, for example, the role of postnatal care.  We need to conduct and examine data from retrospective clinical trials to be sure.  Secondly, when we conduct such experiments we need to ensure that they are adequately powered.  In other words, the number of mice that are used needs to be sufficiently large in order to say with any confidence that the observed effect of a drug is not an experimental artefact.  In my opinion, based on the data presented, this study is underpowered.  I would caution against exaggerating its significance and urge mums-to-be to follow clinician advice.

Paracetamol is currently the go-to medication for pain relief and fever in pregnant women. However, the perceived safety of analgesic use in pregnancy is based on findings relating to the absence of birth defects, toxicology, and maternal and early neonatal well-being; i.e., entirely on antenatal and early postnatal clinical data. Long-term postnatal outcomes including reproductive behaviours have not previously been extensively assessed. The prenatal brain is particularly vulnerable as during this period several critical regions of the brain are forming and connecting to other regions. Therefore, factors that would generally not impact an adult brain could have severe effects on the developing prenatal brain. The Zika virus is a good example of how an external factor has no effect on the adult brain but devastating effects on the fetal brain.

In the current study, paracetamol was given to pregnant mice every day from gestational day seven to birth (this is equivalent in humans to taking paracetamol every day during the second trimester of pregnancy).

They found that prenatal exposure to paracetamol decreased the number of brain cells present in a part of the brain that regulates sexual behaviour in males, called the sexually dimorphic nucleus (SDN). Importantly, the SDN is also present in the human brain where it serves a similar function, therefore these findings translate to humans. Furthermore, sexual and aggressive behaviours were also altered by paracetamol exposure.

This is highly important research that suggests that chronic paracetamol use during pregnancy could cause significant developmental disturbances in the unborn child that may not become apparent until later in life. The research would suggest that Australian pregnant women should take caution when taking regular pain relief medication and consider the long-term impact these medications may be having on their developing child.

This is a carefully described, well-executed study by an international group of scientists, but I am doubtful if it should lead to any change in clinical advice to pregnant women beyond the obvious advice of not to take any drugs in pregnancy unless essential. It has one important design limitation (dose of paracetamol and duration of administration) that makes it unlikely to be relevant to pregnant women.

The authors have examined the effects of two doses of paracetamol administered from the seventh day of pregnancy until birth on neuronal numbers in specific brain nuclei related to sexual behaviour, and on sexual behaviour when the animals were studied at eight weeks postnatal age.

One dose (50 mg/kg body weight/day) was chosen as being towards the upper limit in clinical use. The other dose was three times larger, calculated from body surface area comparisons between mice and humans. This is considered the more appropriate way to calculate dose comparisons by some authorities e.g. the US Federal Drug Administration. Both doses were administered by gavage. This involves placing a tube into the animal’s stomach and administering the drug via this tube. In spite of a commendable amount of experimental detail in the paper, it lacks one crucial piece of information, namely, the period over which the drug was administered. In the absence of this information it seems likely that it was over a period of minutes rather than the 24 hours corresponding to the period when the drug would have been administered clinically (usually every six hours). Thus, the animals, on a body weight basis, appear to have been exposed to considerably more of the drug in a short period than would occur clinically. In any case, this lower dose did not have any effects on brain structure or behaviour. The higher dose did have such effects, but if given over a short period is, again, not comparable to the clinical condition.

It is also relevant that the doses of paracetamol chosen were towards to maximum that would be used clinically. But these are usually used only in conditions such as osteoarthritis. Such large doses are unlikely to be taken by pregnant women.

Having shown an effect with a single large dose based on body surface area it would be of great interest to examine the effects of divided doses (six hourly) that were more akin to those likely to be used by pregnant women. Shorter periods of exposure to paracetamol also need to be studied. Most pregnant women will not be taking paracetamol throughout most of their pregnancy, unlike the mice in this study.

In the meantime it is to be hoped that pregnant women who have taken the occasional tablet of paracetamol because they have a headache or fever will not be alarmed by this study.