There are several points that need to be made in relations to the Consensus Statement published in Nature Reviews Endocrinology. importantly, it does not contain any new research findings but rather a review of the currently available evidence. It evaluates the effects of taking Paracetamol (also known as acetaminophen) during pregnancy on various adverse childhood outcomes, including neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, language delay and decreased IQ. Other possible adverse consequences of paracetamol use in pregnancy may manifest as structural malformations, such as urogenital malformations, especially in boys (undescended testes) and early puberty in girls.

There are two broad areas of research that support these findings: animal studies and large retrospective studies in humans. There are numerous reports that support the notion that paracetamol may act as an endocrine disrupting compound and lead to various abnormalities in animals, mostly rodents. This includes adverse outcomes related to reproductive system as well as behavioural abnormalities in offspring that are exposed to paracetamol in utero. The main limitation of these studies is that rodents are not human and have different physiology, and therefore applying these findings to humans must be made with caution. It is also worth noting that studies done in animals commonly use high doses of the drug under study, often an order of magnitude higher than is typically used in humans. Therefore, while animal studies may demonstrate an adverse outcome and may help explain its mechanism, they are usually not directly translatable to humans.

Studies done in humans are limited by their retrospective design, they look backwards in time, and therefore while they may show an association, they can never prove causation. This can be demonstrated by looking at the circumstances when paracetamol is used in pregnancy. One of the recognised indications is to treat fever. A retrospective study might conclude that use of paracetamol causes adverse outcomes in offspring of women who used it to treat fever. It is possible that having fever per se results in these adverse outcomes, rather than paracetamol used. There are multiple other issues associated with retrospective study design called biases which may misrepresent the true picture. These include selection bias, recall bias, among many others. Various statistical techniques are used in research to address these shortcomings, none of which are completely effective.

What conclusions can be drawn from the body of research that the authors of the study relied upon? It is possible and even likely that paracetamol, if used in excessive quantities and for a long period of time during pregnancy, may have undesirable consequences for the offspring. The risks of occasional and short-term use are probably minimal but high doses and prolonged therapy should be avoided, as is the case for most medications. It must be noted that treating fever and pain during pregnancy is challenging, since most other therapeutic options have significantly higher proven risks compared to paracetamol. The current recommendation for all medications used in pregnancy is to utilise them judiciously, for specific indications, at the lowest possible effective dose and for the shortest period of time. These general principles certainly apply to paracetamol.

Paracetamol is widely used for pain relief and control of fever. It is considered a safe drug to use during pregnancy, where there are few safe options. A recent paper in nature has called for a re-evaluation of paracetamol use in pregnancy based on a variety of lines of evidence. We should be periodically re-evaluating medicine safety, especially drugs for pregnancy, since the developing child is vulnerable. However, we should also be careful not to unduly cause anxiety, and the use of any drug is a balance of benefits vs potential harms.

For example, fever is an accepted risk factor for harm to the developing child, and paracetamol is one of the few available drugs that can be used to reduce fever in pregnancy.

The paper examines both experimental animal studies and observational studies. The animal studies generally use substantially higher doses of paracetamol for longer periods of time than relevant to most human use and not all the animal studies give the same results. Despite these experimental conditions being not immediately applicable to human use, they can give guidance to more focused human studies.

The observational studies are difficult to interpret, while they are suggestive, the same effects have been variously attributed to other environmental influences from Perfluoroalkyl substances to a range of other environmental endocrine disruptions. Teasing out any effect of paracetamol will require new studies, as the authors suggest. Again, as with the animal studies, not all the studies show the same effects.

The authors call for a focused research effort and increasing awareness among health professionals and pregnant women. However, the European Medical Authority already states that "paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency." This advice is consistent with the current guidance from The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

With the current evidence, judicious use of paracetamol is warranted, as always however, women should discuss any concerns with their physicians.