I recently published a letter to the editor about acetaminophen (paracetamol) use and autism spectrum disorders (ASD). We could not afford the fee to make the paper open access.
I wrote about a recent discovery that showed ill effects on children’s neurodevelopment if their mothers used acetaminophen during pregnancy. Ibuprofen use during pregnancy was not associated with neurodevelopmental changes.
Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Dec;42(6):1702-13. doi: 10.1093/ije/dyt183. Epub 2013 Oct 24.
The authors documented the detrimental role that gestational acetaminophen (paracetamol) exposure has on childhood neurodevelopment, putatively due to oxidative stress. Although the authors did not use the words ‘autism spectrum disorder’ (ASD), clearly some of the adverse neurodevelopmental effects they demonstrated are consistent with ASD.
This is not the first time that acetaminophen use during pregnancy was associated with neurodevelopmental changes. In an ecological analysis, Bauer and Kriebel found a strong correlation between use of acetaminophen and prevalence of ASD.
If acetaminophen causes ASD, and if oxidative stress is the mechanism, then the antioxidant capability of the mother and child would be key to explaining why some exposed children develop ASD and some do not.
The authors thought the mechanism of action of acetaminophen toxicity is oxidative stress. It turns out that one of the metabolic pathways of Tylenol causes a lot of oxidative stress. There are three main antioxidant systems in the body, superoxide dismutase, glutathione reductase, and glutathione peroxidase.
Activities of all 3 of these antioxidants are strongly associated with serum vitamin D levels. In a randomized controlled trial of 48 pregnant women, vitamin D supplementation increased total plasma antioxidant capacity (P.0.002), and total glutathione concentrations (P.02) compared with controls. Another randomized controlled trial of vitamin D3 found that it increased human antioxidant capabilities. Thus, the fetuses of vitamin D-deficient mothers would be less able to bear the oxidative stress caused by gestational acetaminophen exposure.
A recent review concluded that vitamin D deficiency may be a major risk factor for ASD, in part due to lack of the antioxidant properties of vitamin D. Three recent studies, using community controls, have found that vitamin D levels are significantly lower in children with ASD. Two of the studies (Mostafa et al. and Gong et al.) also found that ASD severity, as rated on standard ASD rating scales, is inversely correlated with vitamin D levels. Mostafa et al. found an R value of. 86 for the association of serum vitamin D with ASD severity on rating scales.
This model (oxidative stress triggering ASD in vitamin D-deficient pregnant women and young children) is one of the theories of ASD with significant support. Other insults that increase oxidative stress are implicated in ASD, such as infections, toxins, fever and inflammation. It may be that acetaminophen exposure is one of several oxidative stressors that trigger ASD development in vitamin D-deficient pregnant women and young children.
I think the evidence is convincing enough to warn people away from using acetaminophen, especially pregnant women and children.