Paracetamol linked to higher autism risk

In one of the more rigorous studies of its kind, researchers have found paracetamol use by pregnant women is linked to a higher risk of autism in their kids.

The finding, published in the journal JAMA Psychiatry, builds on recent studies in Spain and Denmark that also linked autism with maternal paracetamol use.

Those studies, however, shared a common weakness – they relied on the mothers’ self-reports to calculate total paracetamol use, a technique prone to error.

To sidestep any questions around fallible reporting, the current team, led by paediatrician Xiaobin Wang at the Johns Hopkins University Bloomberg School of Public Health in Baltimore, US, measured paracetamol levels in blood taken from the umbilical cord at birth.

Wang’s group analysed 996 children born to mothers enrolled in the Boston Birth Cohort, a study of single, non-IVF births starting in 1998 and finishing up in 2018.

The original study included more than 3000 mums and babes. Wang’s subset was chosen because there was enough cord blood remaining to do the necessary tests.

In the Boston study children were tracked for up to two decades with tests that, in some cases, included screens for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).

Wang’s team gathered up those data and got down to work.

They started by testing the cord blood samples for paracetamol and two of its breakdown products. Results in hand, they calculated how much drug the foetus had been exposed to in the period around birth, dividing those levels into low, medium and high.

As a double check, they zeroed in on other things that raise autism risk and might confuse the picture, including greater maternal age and weight, fever during pregnancy, extreme prematurity and very low birth weight.

Adjusting for those potential confounds, they crunched the numbers on any connection between paracetamol levels in cord blood and later diagnoses of ASD and ADHD.

The results raise the temperature on an already uncomfortably warm debate.

Babies in the high paracetamol group had a nearly fourfold increase in the odds of having ASD compared to those in the low paracetamol group. Being in the high paracetamol group also raised the odds, by nearly threefold, of a later diagnosis of ADHD.

“[C]ord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion,” the authors write.

Notwithstanding the usual caveat that correlation does not equal causation, what might be creating this effect?

How paracetamol works is surprisingly complex, given its wide use, but it is known to inhibit an enzyme called cyclooxygenase, or COX, as part of its anti-inflammatory and painkilling effect.

COX inhibition has been linked to problems with brain plasticity and spatial learning in rats. And paracetamol itself has been directly implicated in brain cell death in rodents.

The study is not without limitations. Paracetamol levels drop by half every three hours, so the cord blood samples only reflect paracetamol taken by mums around the time of birth and not throughout pregnancy.

Nonetheless, the authors point out this is an important period.

“Animal experiments suggest that the perinatal period is the critical exposure window for acetaminophen to induce behavioural abnormalities in mice,” they write.

There are, however, further concerns with the study.

“Only those children who had neurodevelopmental testing, which was not routine for the whole cohort, were included in the analysis,” says Alex Polyakov, Clinical Director at Melbourne IVF and Royal Women’s Hospital, Australia, who was not involved in the study.

“This significant selection bias is evident in extremely high prevalence of all neurodevelopmental conditions in this cohort, with only 32.8% of children that were included in this study not receiving a diagnosis of either ADHD, ASD, developmental disability or some combination of the three,” he says

“Therefore, the applicability of the study’s findings to [the] general population, where the prevalence of neurodevelopmental conditions is generally accepted to be less than 5%, is highly questionable.”

Norman Saunders, a developmental neurobiologist at the University of Melbourne, who was not involved in the study, points out that “there was no pregnant patient group who had not taken paracetamol”.

The lack of such a control group makes it hard to isolate paracetamol as the cause of the claimed effects. Saunders is also sceptical of the brief window of paracetamol use the study captures.

“[W]e know nothing of when else during pregnancy the paracetamol might have been taken. It is possible, but seems unlikely, that a few tablets of paracetamol taken around the time of birth would cause problems,” he says.

What, then, is the best course of action for expectant mothers?

“Nothing in this study indicates that an occasional intake of a couple of Panadol tablets while pregnant would have any effect on the risk of ADHD/ASD,” says Polyakov, before adding a caveat.

“Like any medication, paracetamol is not risk free and should only be taken if necessary, especially in pregnancy. Based on this study’s findings it may be best to avoid paracetamol around the time of labour and delivery,” he says.

Saunders also counsels caution:

“The current official advice in Australia (e.g. Australian Medicines Handbook, 2019) is that paracetamol is ‘safe’ to use in pregnancy and breastfeeding. In the light of this and other published information, it is high time for this advice to be modified.”