Silvia Alemany is a senior researcher (Miguel Servet fellow) at the Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Barcelona (Spain), investigating genetic and environmental risk factors and their interaction in mental health.
A frequent drug
Most women experience headache, flu or even infections while they are pregnant. In this special period of their lives they care a lot about their own health but also (and usually a lot more!) about their baby’s health. Pregnant women reconsider what they eat, what they drink and their habits in order to provide the best environment for their future babies. In this regard, most health professionals rely on paracetamol as one of the few safe drugs to use during pregnancy. Indeed, despite pregnant women being reluctant to use drugs, paracetamol (or acetaminophen) is used by 46–56% of pregnant women in developed countries [1].
Potential long-term effects: Paracetamol use linked to neurodevelopmental disorders
Evidence from the last decade indicates that prenatal (before birth) exposure to paracetamol might have negative effects on the development of the foetus [1]. Evidence from epidemiological studies suggest that prenatal paracetamol use is associated with slightly worse cognitive performance, behavioural problems, Autism Spectrum Disorders (ASD) and Attention-Deficit and Hyperactivity Disorder (ADHD) symptoms among children [2]. These findings challenge the widely accepted view of paracetamol as a safe drug during pregnancy.
Most of these studies are based on birth-cohorts including hundreds or thousands of pregnant women. In these studies, researchers collect information during pregnancy and then follow the development of the children. This type of longitudinal data allows us to examine the consequences of early exposures and reduce the effects of many confounders. For instance, most studies based on birth-cohorts controlled for fever during pregnancy. Fever itself may also (negatively) influence brain development of the foetus, but it is also closely related to paracetamol use.
In a recent meta-analysis, we jointly analysed data from 6 European birth cohorts representing 73,881 mother–child pairs and we found that children exposed to paracetamol before birth were 19% more likely to develop autistic symptoms and 21% more likely to develop ADHD symptoms than children who were not exposed [2]. Although these results are concerning, the studies from this meta-analysis do have several limitations. For instance, we do not have information about the exposure paracetamol itself, since many studies lack relevant information such as frequency or duration (how many times a day? For how many days?) of use or doses. We also do not fully understand the mechanisms that link paracetamol use to alterations in brain development. More knowledge about use, dosages, mechanisms and causal factors is needed in order to properly inform mothers and health professionals.
Is paracetamol use during pregnancy causing neurodevelopmental problems in children?
Considering the current evidence, paracetamol use during pregnancy is not a sufficient or necessary cause for ASD or ADHD. Both ASD and ADHD are complex disorders that arise from a combination of several risk factors. That said, from what we know now of the effects of paracetamol use during pregnancy, there are certain indications that it could play a causal role in brain development. 1) Temporality: from the longitudinal data we know that the exposure to paracetamol took place before the neurodevelopmental problems were observed. But note, alterations in brain development that ultimately lead to ADHD or ASD could have already started before the paracetamol use. 2) Consistency: many studies using different methods, from different countries showed similar results. 3) Biological plausibility: there are several biological mechanisms that could explain potential harmful effects of paracetamol during foetal development. These need to be further investigated. 4) Dose-response relationship: it has been shown that the higher the dose of paracetamol during pregnancy, the larger the effects on the child. But as mentioned above, we need to gain more knowledge about this.
This warrants the need for more research on the effects of paracetamol and inform society and health professionals of the current evidence.
Can I use paracetamol if I am pregnant?
In a recent consensus statement from several experts, “pregnant women should use paracetamol with caution at the lowest effective dose for the shortest possible time” [1]. Moreover, we believe that its use should be medically supervised whenever possible. That said, pregnant women using paracetamol now or in the past should not worry or feel guilty (that is not our message!). As abovementioned, neurodevelopmental disorders are caused by a complex interplay of many different factors. Even more important, general health of the mother is also very important for the development of the child, and not treating fever could have worse effects during pregnancy than paracetamol use. We therefore advise pregnant women to always consult their doctor for advice.
References
[1] Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag CG, et al. Paracetamol use during pregnancy – a call for precautionary action. Nat Rev Endocrinol 2021;17:757–66. https://doi.org/10.1038/S41574-021-00553-7.
[2] Alemany S, Avella-García C, Liew Z, García-Esteban R, Inoue K, Cadman T, et al. Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. Eur J Epidemiol 2021;36:993–1004. https://doi.org/10.1007/S10654-021-00754-4.