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By Children’s Health Defense Science Team
Evidence has emerged over the past two decades pointing toward exposure of susceptible babies and children to acetaminophen as a factor leading to autism spectrum disorder (ASD).
Prior to this study, published on Preprints.org and authored by the Children’s Health Defense (CHD) science team, scientific literature has supported the theory that neurodevelopmental risks from acetaminophen exposure are greatest during the peripartum period, and decrease over time as the child ages, dissipating by age 6. Risk during pregnancy, although possibly lower than post-partum risk, is still probably significant.
Unfortunately, many researchers have underestimated or even overlooked entirely the contribution of acetaminophen to the prevalence of ASD, in large part due to errors in adjusting for confounding factors, and because they focused on pregnancy, when the risks of ASD induction may be lower.
The first study probing the connection between acetaminophen use and ASD was published by Schultz in 2008. That study suggested that the vast majority of all cases of regressive ASD might be attributed to acetaminophen exposure. Although the study has been criticized, a detailed analysis reveals that those criticisms are not valid.
The Schultz study adds to independent studies from pregnancy and from the peripartum period, strengthening the link between acetaminophen use and ASD.
However, other than the Schultz study, few additional studies have addressed the association between acetaminophen use and regressive ASD, with a major limitation being that the use of acetaminophen in early childhood is often not documented.
‘Very strong associations’ between typical childhood illnesses and autism
CHD scientists investigated the association between ASD and medical conditions that normally result in acetaminophen exposure during childhood. For this purpose, we evaluated associations between ASD and the occurrence of several conditions involving fever and/or pain using the Florida Medicaid database.
We demonstrate remarkably strong associations between repeated documentation of “acetaminophen exposure surrogates” and ASD.
A surrogate refers to a condition for which someone would take acetaminophen to alleviate the symptoms. Surrogates to acetaminophen use were derived from package inserts and labels of acetaminophen, and were defined as dental work, earache, sinusitis, sore throat, tonsillitis or laryngitis, upper respiratory tract infection, fever, and flu.
We used data from Florida’s state Medicaid program for our analysis. In all, data for 674,785 children born between 1990 and 2005 who had at least one Medicaid diagnosis of any kind in their first year of life, and one diagnosis at or after age 6 years were included in the analysis.
This is an extremely conservative approach, as we are excluding people with no medical diagnoses in their later childhood to ensure that we are not including children who are enrolled but do not interact with the Medicaid system.
Children were 126% more likely to develop ASD if they had at least one surrogate, compared to those with no surrogates. Increasing the number of minimum acetaminophen exposure surrogates in the analysis increased the risk considerably, indicating that multiple surrogates imposed considerably more risk than single surrogates.
At four different surrogate diagnoses, the risk went up to 163% more likely to develop ASD.
The risk did not differ significantly between boys and girls when all surrogates were investigated together. However, when fever (one of the most common reasons for childhood acetaminophen use) alone was inspected, girls had a significantly different and greater risk of developing ASD if they were diagnosed with a fever.
Boys with one fever diagnosis had a 56% increased risk for ASD, and boys with four fever diagnoses had a 184% increased risk. In stark contrast, girls with one fever diagnosis had a 79% increased risk for ASD, and girls with four fever diagnoses had a 266% increased risk.
The present results demonstrate very strong associations between typical childhood illnesses and ASD, with a very strong sex-linked signal. The stronger association with girls than with boys appeared to be a result of fewer girls than boys without ASD having documented acetaminophen exposure surrogates.
However, in this research, as in many previous studies, ASD was predominantly observed in males, a fact reflected by several laboratory animal studies showing that males are more susceptible to acetaminophen-mediated neurodevelopmental injury than are females. These studies are Dean, et al., 2012; Kanno, et al., 2017; Rigobello, et al., 2021; and Baker, et al., 2023.
Children most likely to be injured by acetaminophen are most likely to be exposed to the drug
This analysis does not probe the causal relationship between acetaminophen exposure and ASD. A causal relationship has been inferred from a large and robust body of evidence: Good, 2009; Good, 2018; Shaw, 2013; Patel, et al., 2022; Zhao, et al., 2023; Parker, et al., 2023; Jones, et al., 2024.
However, our research is not designed to address that issue. Rather, this research was conducted to probe the relationships between ASD and the occurrence of childhood illnesses that typically involved treatment with acetaminophen.
Previous studies, including Sabourin, et al., 2019, and Karlsson, et al., 2022, have shown that individuals with ASD tend to have more childhood infections than individuals without ASD, with odds ratios lower than 2.0 (or less than doubling of the risk).
The present research shows that removing individuals with fewer number of diagnoses from the analysis dramatically increases the risks for ASD. Thus, it seems likely that the higher odds ratios we observed compared to previous studies are due to multiple occurrences of acetaminophen exposure surrogates.
This suggests that multiple exposures to acetaminophen may be important in the etiology of ASD.
A next step in this work will be to evaluate the risks of ASD as a function of the number of diagnoses and the type of diagnoses.
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The current data are sufficient to infer that four or more diagnoses are associated with greater risk than three or fewer diagnoses.However, whether the risk of ASD plateaus with a particular number of diagnoses remains to be seen.
Further, it remains unknown whether particular diagnoses — for instance, sinusitis versus ear infection — are associated with more risks than others.
It is recognized that immune activation and oxidative stress render acetaminophen more dangerous due to its pharmacological properties. Unfortunately, individuals with inflammation and oxidative stress are more likely to be exposed to acetaminophen, creating a dangerous situation in which those individuals most likely to be injured by acetaminophen are the individuals most likely to be exposed to the drug.
This research adds further to that knowledge, beyond the established peripartum studies, such as cord blood biomarkers and circumcision, on ASD incidence, suggesting that individuals with multiple exposures to acetaminophen may be particularly at risk.