No strong evidence ties use to autism or ADHD risk

Existing evidence does not clearly link paracetamol (acetaminophen) use during pregnancy with autism or ADHD in children, finds an in-depth evidence review published by The BMJ today, in direct response to recent announcements around the safety of using paracetamol in pregnancy.

The researchers say confidence in the findings of existing evidence reviews and studies on this topic is low to critically low, and suggest that any apparent effect seen in previous studies may be driven by shared genetic and environmental factors within families.

Regulatory bodies, clinicians, pregnant women, parents, and those affected by autism and ADHD should be informed about the poor quality of the existing reviews and women should be advised to take paracetamol when needed to treat pain and fever in pregnancy, they add.

Paracetamol (acetaminophen) is the recommended treatment for pain and fever in pregnancy and is considered safe by regulatory agencies worldwide.

Existing systematic reviews on this topic vary in quality, and studies that do not adjust for important factors shared by families or parents’ health and lifestyle cannot accurately estimate the effects of exposure to paracetamol before birth on neurodevelopment in babies.

To address this uncertainty, researchers carried out an umbrella review (a high-level evidence summary) of systematic reviews to assess the overall quality and validity of existing evidence and the strength of association between paracetamol use during pregnancy and the risks of autism or ADHD in offspring.

They identified nine systematic reviews that included a total of 40 observational studies reporting on paracetamol use during pregnancy and the risk of autism, ADHD, or other neurodevelopmental outcomes in exposed babies.

Four reviews included meta-analysis (a statistical method that combines data from several studies to give a single, more precise estimate of an effect).

The researchers used recognized tools to carefully assess each review for bias and rated their overall confidence in the findings as high, moderate, low, or critically low. They also recorded the degree of study overlap across reviews as very high.

All reviews reported a possible to strong association between a mother’s paracetamol intake and autism or ADHD, or both in offspring. However, seven of the nine reviews advised caution when interpreting the findings owing to the potential risk of bias and impact of unmeasured (confounding) factors in the included studies.

Overall confidence in the findings of the reviews was low (two reviews) to critically low (seven reviews).

Only one review included two studies that appropriately adjusted for possible effects of genetic and environmental factors shared by siblings, and accounted for other important factors such as parents’ mental health, background, and lifestyle.

In both these studies, the observed association between exposure to paracetamol and risk of autism and ADHD in childhood disappeared or reduced after adjustment, suggesting that these factors explain much of the observed risk, say the researchers.

They acknowledge some limitations. For example, the included reviews differed in scope and methods, they were unable to explore the effects of timing and dose, and their analyses were limited to autism and ADHD outcomes only.

However, they say this overview brings together all relevant evidence and applies established methods to assess quality, and shows “the lack of robust evidence linking paracetamol use in pregnancy and autism and ADHD in offspring.”

They conclude, “The current evidence base is insufficient to definitively link in utero exposure to paracetamol with autism and ADHD in childhood. High quality studies that control for familial and unmeasured confounders can help improve evidence on the timing and duration of paracetamol exposure, and for other child neurodevelopmental outcomes.”