Pregnancy paracetamol use and offspring ADHD traits?

Poor old paracetamol (acetaminophen if you wish).

Tablets (before tablets again) @ Wikipedia

First it was the Brandlistuen correlation [1] suggesting that sustained exposure in-utero may impact on childhood developmental outcome (see here for my take). Now another swipe has been taken at this pharmaceutical stalwart of pain relief / fever reduction with the publication of results by Zeyan Liew and colleagues [2] suggesting that: "Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children". HKDs by the way, refer to hyperkinetic disorders which includes the diagnosis of attention deficit hyperactivity disorder (ADHD) (see here).

Given what the Liew results suggested, together with the impact of the publishing journal (the journal family of which currently carries some interesting news about US pediatric obesity rates), it's little surprise that headlines such as: 'Acetaminophen use in pregnancy may be linked to ADHD ' and sub-headings like: 'Moms-to-be who relieve pain with acetaminophen may be setting their children up for hyperactivity' have appeared all around this work.

Reliant on data from another Scandinavian registry - the Danish National Birth Cohort [3] - (no, not MoBa), researchers looked at data covering nearly 65,000 children whose mothers were asked to report on paracetamol use during pregnancy and parent-reported "behavioral problems in [offspring] children 7 years of age". They used a variety of materials to ascertain the presence or not of those HKDs and ADHD-like behaviours including the Strengths and Difficulties Questionnaire and diagnostic and prescription information related to ADHD.

The results: "More than half of all mothers reported acetaminophen use while pregnant". Nothing particularly unusual about this fact given that paracetamol enjoys a place in most medicine cabinets as a drug of choice when it comes to pain relief and/or fever. But then the correlations: "Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27)". That and the fact that something like a dose-response relationship seemed to be emerging from the collected data, and one has a story that will make most readers sit-up to attention.

The accompanying editorial on the study [4] is also worthwhile reading so as to emphasise that correlation is not the same as causation and the important requirement to replicate this experiment before drawing too many conclusions at this time. As I mentioned in my post on the previous paracetamol - childhood outcomes study, asking participants about their use of commonly available medicines like paracetamol during pregnancy (even prospectively) is not the same as looking at prescriptions data based on frequency and dosage (as the authors did in relation to the use of something like methylphenidate as a proxy for subsequent offspring ADHD diagnosis/behaviours).

That being said, alongside the Brandlistuen results (which themselves have been discussed in the peer-reviewed forum [5]) this latest data add to a worrying trend when it comes to paracetamol use during pregnancy. How, just because it is an over-the-counter (OTC) medicine, this does not mean one should treat it with any less care than a prescription drug.

The good thing, if there is any good thing to come out of this study, is that unlike the growing pains of the emerging valproate - childhood development story, paracetamol is for pain relief and not a must-take medicine for a must-treat condition like epilepsy. Granted, one has to be careful about the alternatives to paracetamol (as per the dos and don't of ibuprofen use during pregnancy) but I'm sure that other solutions can be found during the nine months that made you? [6] (open-access).

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[1] Brandlistuen RE. et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Dec;42(6):1702-13.

[2] Liew Z. et al. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. 2014; February 24.

[3] Olsen J. et al. The Danish National Birth Cohort - its background, structure and aim. Scand J Public Health 2001; 29: 300-307.

[4] Cooper M. et al. Antenatal Acetaminophen Use and Attention-Deficit/Hyperactivity Disorder
An Interesting Observed Association But Too Early to Infer Causality. JAMA Pediatr. 2014; February 24.

[5] Cannell JJ. Paracetamol, oxidative stress, vitamin D and autism spectrum disorders. Int J Epidemiol. 2014 Feb 11.

[6] Lewis AJ. et al. Early life programming as a target for prevention of child and adolescent mental disorders. BMC Medicine 2014; 12: 33

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Zeyan Liew, Beate Ritz, Cristina Rebordosa, Pei-Chen Lee, & Jørn Olsen (2014). Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2013.4914