Prenatal paracetamol exposure and offspring outcome

Pain. Nobody particularly likes it, but with the pharmaceutical arsenal of pain relief medication at our disposal these days, many cases of pain can be tackled in one way or another.

Tablets (before tablets) @ Wikipedia 

For those who watched the recent BBC series by the ever-intrepid Dr Michael Mosley titled 'Pain, pus and poison' on some of the important history behind the modern medical, chemical and pharmacy professions, pain was a feature of quite a few of the developments discussed.

Indeed, it was a real eye-opener to learn that one of our most famous forms of pain relief - aspirin - was at one time rejected in favour of another equally famous drug, heroin (see here for the background to the Bayer story).

With pain relief medication in mind, today I'm talking about the paper by Brandlistuen and colleagues* who reported: "Children exposed to long-term use of paracetamol during pregnancy had substantially adverse developmental outcomes at 3 years of age". Some of the accompanying media about this study can be found here.

Paracetamol or acetaminophen to our cousins over the Pond, has a special place when it comes to modern pain relief. Not only does it have pain relief (analgesic) qualities but its antipyretic (fever reducing) properties also add an extra dimension to this widely available pharmaceutic. As the pin-up drug for pain relief, paracetamol also has a bit of dark side too. Paracetamol overdose is, unfortunately, an all too common occurrence these days**; on some occasions without users even realising that they've overdone it (see here). And just in case you were wondering, it is a really horrible way to leave this mortal coil (see here).

Brandlistuen et al relied on data derived from the Norwegian Mother and Child Cohort Study otherwise known as MoBa which some readers might remember from a recent post on this blog (see here). They asked pregnant women about their paracetamol usage at various stages of their pregnancy and a few months after they had delivered. Relying on a comparison between sibling pairs (one exposed to paracetamol during pregnancy and the other unexposed), data on 2919 same-sex sibling pairs were analysed in relation to aspects of "psychomotor development" and things like temperament.

The results suggested that "children exposed to prenatal paracetamol for more than 28 days had poorer gross motor development [β 0.24, 95% confidence interval (CI) 0.12-0.51], communication (β 0.20, 95% CI 0.01-0.39), externalizing behaviour (β 0.28, 95% CI 0.15-0.42), internalizing behaviour (β 0.14, 95% CI 0.01-0.28), and higher activity levels (β 0.24, 95% CI 0.11-0.38)". Sorry for the very long quote but basically quite a few problem issues seemed to be more readily reported in the exposed siblings compared with unexposed control siblings.

Importantly, researchers were to a large extent able to rule out other pain relief medication such as ibuprofen, as being related to these findings and by doing so also to some degree answer the question of "whether the underlying illness could be the cause of the effect on the children, and not paracetamol itself".

This is not the first time that paracetamol usage during pregnancy has come under the research spotlight. Outside of the growing research base correlating pregnancy paracetamol use and a heightened risk of offspring asthma***, there have been murmurs down the years that other aspects of offspring development might also be associated with pregnancy paracetamol use; although nothing as methodologically strong as that of the Brandlistuen results.

I was always going to be interested in the Brandlistuen findings given my previous discussion on the issue of sulphation (or sulfation if you prefer) in relation to autism (see here and here). It is more of a peripheral connection than anything based on the way that medicines such as paracetamol are metabolised in the body**** and what happens when one of the major paracetamol processing pathways is disrupted in some cases of autism*****. That and the continuing interest in all things NAC and autism (see here).

In more recent times I've however noted quite a bit of speculation on how paracetamol use might have a more 'direct' effect on the autism numbers game as per the paper by Bill Shaw****** (open-access) which has received quite a lot of attention (see here). This bearing in mind, that Dr Shaw was not the first to suggest a connection as per the paper by Bauer and Kriebel******* (open-access). That and the quite controversial suggestion by Schultz and colleagues******** that: "acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder" perhaps enquiring whether the issue of fever suppression might also be something to look at as per the speculations of Torres********* (open-access).

Stepping back a little, there are a few cautions to take before reading too much into this area of research interest. As the authors note in the accompanying press on this work: "Importantly, we cannot assume that there is a causal relationship between maternal use of paracetamol during pregnancy and adverse effects in children from an epidemiological study". I'd second that notion of correlation not necessarily being the same as causation. The use of 'maternal report' for paracetamol usage is also probably going to be subject to some degree of bias. Scoring for example, when you took a pill and noting its brand and strength is not the same as looking at doctor prescriptions or pharmacist notes, even without the issue of medication adherence to contend with too.

As far as I can see, the Brandlistuen results did not mention autism as an outcome measure from their trial so one has to be careful of making any sweeping generalisations to the autism spectrum based on this particular study. I've mentioned autism in this post because of that potential sulphation research link but imply nothing more at present.

The Brandlistuen work also talked about quite chronic exposure to pregnancy paracetamol use (more than 28 days) as showing the stronger association over shorter exposure periods, which could be interpreted as a dose-response relationship. In a real-life setting and understanding that medicines, all medicines, have the propensity for side-effects, one might look at alternative methods of pain relief during pregnancy or some all-important medicines management as being key to balancing why medication is needed vs. potential risks or side-effects as per what needs to be done with other medicines taken during pregnancy. Did I also mention correlation is not the same as causation?

I'm reserving my last words on this post with a reiteration of my oft-cited caveat on this blog about not giving medical or clinical advice. If you need to talk to someone about this issue and the concept of risk, have a chat with your medical healthcare provider.

To close, for any Pharmacists out there: do you fancy a trip to the House of Fun? (This is a chemists, not a joke shop)

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* Brandlistuen RE. et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Oct 24.

** Hawton K. et al. Impact of different pack sizes of paracetamol in the United Kingdom and Ireland on intentional overdoses: a comparative study. BMC Public Health 2011; 11: 460.

*** Andersen AB. et al. Use of prescription paracetamol during pregnancy and risk of asthma in children: a population-based Danish cohort study. Clin Epidemiol. 2012; 4: 33-40.

**** Jensen LS. et al. The quantification of paracetamol, paracetamol glucuronide and paracetamol sulphate in plasma and urine using a single high-performance liquid chromatography assay. J Pharm Biomed Anal. 2004 Feb 18;34(3):585-93.

***** Alberti A. et al. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4.

****** Shaw W. Evidence that Increased Acetaminophen use in Genetically Vulnerable Children Appears to be a Major Cause of the Epidemics of Autism, Attention Deficit with Hyperactivity, and Asthma. Journal of Restorative Medicine 2013; 2: 1.

******* Bauer AZ. & Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 2013; 12: 41.

******** Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

********* Torres AR. Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatr. 2003; 3: 9.

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Brandlistuen RE, Ystrom E, Nulman I, Koren G, & Nordeng H (2013). Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. International journal of epidemiology PMID: 24163279