Prenatal paracetamol & neurobehavioural harms

US researchers have found an association between prenatal exposure to paracetamol and neurobehavioural issues emerging in children by the age of three.

While paracetamol is recommended during pregnancy, especially to reduce fever, meta-analyses have reported associations between prenatal exposure to paracetamol and neurobehavioural problems in children, including attention-deficit hyperactivity disorders.

The new study, published 28 September 2022 in PLOS ONE, found that in-utero exposure to paracetamol predicted sleep and attention problems in offspring by three years of age, indicating problems with child self-regulation.

The team from Pennsylvania State University looked at 2,423 mother-child pairs and compared the mums’ medication use with childhood behavioural problems using a syndrome scoring instrument called the Child Behaviour Checklist (CBCL), specifically designed for children up to five years of age.

Just over 41% of participants reported using paracetamol during pregnancy and the children who were exposed in-utero scored significantly higher on two of the seven CBCL syndrome scales – sleep problems and attention problems – compared to their paracetamol-free counterparts.

Lead author Kristin K. Sznajder, from Department of Public Health Sciences, Pennsylvania State University College of Medicine, explained that the present study is the first to find predictive association between prenatal paracetamol use and preschool-age sleep problems.

“These findings not only corroborate previous studies reporting associations between prenatal exposure to paracetamol and attention problems in offspring but also show an association with sleep problems at three years of age,” Ms Sznajder said.

“The fact that neurological dysfunction underlies both sleep and attentional issues in children, suggests that an important mechanism of influence may be the impact of paracetamol on prenatal neurology, which may impact the regulation of attention and sleep in the preschool period.

“Because use of paracetamol during pregnancy is common, these results are of public health concern and suggest caution in the use of medications containing paracetamol during pregnancy.

Due to its analgesic, anti-inflammatory, and antipyretic qualities, paracetamol is often taken to reduce pain and fever and may be acquired as an over-the counter medication or a prescription medication, and while their study could not prove cause and effect, as paracetamol is so commonly used during pregnancy the team said that more research is clearly needed.

For example, the use of paracetamol in the first and second trimesters of pregnancy was reported by 69.9% of US women, and a recent Consensus statement estimated that more than 50% of women worldwide used paracetamol while pregnant.

However, despite these latest findings, Australian experts have been quick to advocate for the continued, judicious use of paracetamol during pregnancy, pointing out that pain itself, and the reasons for pain, can be a potential source of harm for both mother and developing child.

Dr Ian Musgrave, a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide explained that a big problem in studies like these is the issue of other conditions or ‘confounders.’

“The mothers who took paracetamol were taking it for issues like fever, infection, and allergies, all of which can potentially affect the mental development of the child,” Dr Musgrave said.

“For example, maternal stress was associated with the child being withdrawn, having sleep problems and attention problems.

“The authors attempted to control for these confounders, but the association of paracetamol with sleep problems and attention problems after this correction is marginal and may simply be due to other factors associated with the need to use paracetamol for pain relief.”

Indeed, scores on all seven of the CBCL syndrome scales were significantly associated with prenatal stress, and the predictive association between paracetamol use and adverse child behavioural outcomes was mitigated but not eliminated after controlling for stress, suggesting that both stress and paracetamol use may independently affect child behavioural outcomes.

Dr Gavin Pereira, a Professor of Epidemiology and Biostatistics at Curtin University said that due to the impact of prenatal stress and other limitations of the study, it remained unclear whether paracetamol taken during pregnancy causes attention and sleep problems in offspring.

“In the US study, these outcomes were assessed by mothers, rather than by a relatively more independent party such as a teacher or clinician,” he explained.

“It is possible that mothers with underlying anxiety are more likely to take paracetamol and report such negative outcomes for their child, whether there is an underlying biological effect.

“Given these issues, along with the fact that the size of the associations observed by the researchers were small and that the researchers could not establish a dose-response relationship, the findings remain unclear,” Dr Pereira said.

“The findings of this study certainly do not imply that common alternatives such as non-steroidal anti-inflammatory drugs (NSAIDs) should be used for pain relief in pregnancy instead of paracetamol – such alternatives may cause more harm.”