This version is not peer-reviewed.
Submitted:
29 January 2025
Posted:
30 January 2025
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“Specifically, in utero (but not postnatal) exposure to paracetamol results in a 19% increased risk of ASD (Masarwa et al., 2018; Alemany et al., 2021; Khan et al., 2022)…”
“It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.”
Evidence / references | Background / additional information |
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1. Mechanisms of APAP-mediated injury are plausible. For review, see Jones et al. [4] | The first study showing that children with ASD are deficient in a metabolic pathway necessary to safely detoxify APAP in babies (sulfation) is now more than a quarter of a century old [79], and was subsequently corroborated [80,81]. One enzyme (CyP450 2E1) which produces the toxic metabolite of APAP (NAPQI) is expressed in the human brain from before birth [82] and is a target of epigenetic alterations in mothers who have children with ASD [83]. In addition, polymorphisms in another enzyme (CyP450 1A2) that produces the same toxic metabolite of APAP is associated with ASD [84,85]. |
2. APAP use during early childhood is associated with a 20-fold greater risk of regressive ASD [16]. | This case-controlled study, now more than 16 years old, has been widely criticized, but careful analysis does not reveal any credible objections [1]. |
3. APAP use with mild adverse reactions to a vaccine, but not mild adverse reactions to a vaccine alone, is associated with ASD [16]. | This study, the same as in line of evidence #2, was the first study to separate the impact of vaccines from APAP on neurodevelopment, and the first to implicate APAP with the etiology of ASD. |
4. APAP was never demonstrated to be safe for neurodevelopment [17]. Over two thousand papers in the medical literature claim that APAP is safe for babies and/or children when used as directed, but all studies were based on the false assumption that adverse reactions in babies would involve easily measured liver injury, the same as in adults [17]. | Like APAP, opioids have also never been shown to be safe for neurodevelopment [86]. However, unlike APAP, opioids are not generally assumed to be safe for neurodevelopment when used as directed. Further, one study probing the safety of prenatal opioid exposure found reductions in communication skills in children associated with prenatal APAP exposure, but not with prenatal opioid exposure [39]. |
5. Numerous studies in laboratory animals from multiple laboratories indicate that early life exposure to APAP causes long term changes in brain function [59,87,88,89,90,91,92,93]. | After adjusting for weight, the amount of APAP that causes profound changes in laboratory animals in some studies is very close to [59] or even less than [87] the amount administered to human babies and children. Thus, APAP could never be used in babies or children if current guidelines for drug safety were applied. |
6. Early life exposure to APAP has a greater long-term impact on male laboratory animals than female laboratory animals [89,92,94]. ASD is more common in males than in females. | The reason or reasons why males are more susceptible to APAP-mediated injury has been considered in some detail, and several plausible mechanisms have been proposed [89,94]. |
7. Prenatal exposure of laboratory rats to APAP causes problems with the processing of sound [11]. Some degree of auditory dysfunction is seen in the majority of individuals with ASD. Reviewed by Graeca and Kulesza [11]. | The investigators found developmental delays with ear opening and, essentially, difficulty with hearing later in life after exposure to APAP as a fetus. It is unknown whether these affects in laboratory animals are related to impairments in some individuals with ASD. |
8. APAP causes apoptosis-mediated death of cortical neurons in laboratory rats [95], and cortical neurons may be involved in the pathology of ASD [96,97]. | Increased levels of biomarkers for neuronal apoptosis [98,99,100] and impaired autophagy [101] are associated with ASD. Autophagy is necessary to clearing damaged organelles such as mitochondria [102], which are created by aberrant metabolism of APAP [103]. |
9. Genetic, epigenetic, and environmental factors associated with an increased risk of ASD have an adverse effect on the body’s ability to safely metabolize APAP [20,79,104]. | The wide array of factors associated with ASD have led to the hypothesis that many things can come together to cause ASD, but ASD is characterized by impairment of social function and other particular behavioral phenotypes, suggesting specificity in the etiology of the condition. |
10. Cystic fibrosis is associated with unusually efficient (effective) metabolism of APAP [105,106], and the prevalence of ASD is apparently very low in patients with cystic fibrosis [20]. | The mental health of patients with cystic fibrosis has been characterized extensively, but no association between ASD and cystic fibrosis has been reported. |
11. APAP temporarily blunts social trust [107] and awareness [108], emotional responses to external stimuli [109], and the ability to identify errors [110] in adults. | Although the mechanisms are unknown, these studies show that APAP affects aspects of mental function that are impaired in individuals with ASD. |
12. Higher le[19,21,22,33–52vels of APAP in cord blood are associated with ASD [21]. | For the analysis, the authors divided the women into three groups based on cord blood APAP levels. The third with the highest levels had 3.6 times more likelihood of having a child with ASD that the third with the lowest levels of APAP. |
13. Use of APAP during pregnancy has been associated with adverse long-term effects on the mental health of offspring in numerous studies [19,21,22,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. | This line of evidence has received more attention than any other line of evidence, to the point of being the only line of evidence considered by many investigators. However, the numerous studies underpinning this line of evidence are hampered by several factors which can cause errors in estimation of the association between APAP and ASD [4]. A recent study found a dramatic association (odds ratio (OR) for ASD with APAP use = 1.8) [23], but incorrectly and completely cancelled out that association using an error in the assumptions underlying the statistical analysis [2,4]. |
14. Analysis of the Danish National Birth Cohort (DNBC) revealed an odds ratio (OR) of 1.3 (CI 1.02–1.66) for ASD associated with postnatal APAP exposure [38], despite the fact that the use of APAP appears to be dramatically underreported in the DNBC [1]. | The study authors averaged the results from the DNBC with assessments of autism-like symptoms (not ASD) from smaller data sets, and reported no association between APAP use and those symptoms (not ASD) in the abstract of the paper [38]. This issue has been addressed in detail by us in the literature [1,2], but unfortunately may still result in confusion [11]. In addition, the study [38] employed invalid statistical adjustments expected to underestimate the association between APAP and ASD [2,4]. See text for additional discussion. |
15. The incidence of ASD began to increase in the early 1980s, coinciding with the increase in APAP use after aspirin was associated with Reye’s syndrome [20] | Temporal associations do not prove causality, but are a necessary prerequisite for causality to exist. Alternative explanations for the rise in prevalence of ASD face several insurmountable problems, previously reviewed [1,4]. |
16. The incidence of ASD has steadily increased [20] as direct-to-consumer advertising [111] and perhaps other factors such as mandated use of APAP with the MenB vaccine (see discussion) have led to increased APAP exposure early in life. | Temporal associations do not prove causality, but are a necessary prerequisite for causality to exist. Alternative explanations for the rise in prevalence of ASD face several insurmountable problems, previously reviewed [1,4]. One possible explanation for the persistence of unrealistic alternative explanations may be that many investigators are unaware of a satisfactory explanation consistent with available evidence. |
17. The ratio of regressive to infantile ASD rose at the same time as pediatric APAP use rose [112] after aspirin was associated with Reye’s syndrome [20]. | This observation, made in 2000, would suggest that something was introduced into the environment that could induce ASD after months or even years of neurodevelopment. This factor was tragically and incorrectly suspected to be a vaccine at that time, an issue that was decisively addressed by Stephen Schultz eight years later (see line of evidence #3). |
18. Circumcision of males is associated with a 2-fold increase in the risk for early-onset (infantile) ASD [60]. | Circumcision is often performed using APAP as an analgesic despite the fact that such use is of highly questionable effectiveness [113]. |
19. The popularity of APAP use and the prevalence of ASD was substantially higher in Denmark than in Finland in the mid-2000s [3]. | Geographic-dependent associations do not prove causality, but do contribute to the total body of evidence. Particularly in the absence of alternative explanations, these associations can be compelling. |
20. An exceptionally high prevalence of ASD was identified in South Korea [114,115] following repeated findings of levels of APAP exceeding the package label of children’s products [116]. | Repeating mistakes made when the initial determination of APAP safety for pediatric use was determined (See line of evidence #4), public health authorities assessed the prevalence of reports of liver failure in the pediatric population, and determined that no harm was caused by the excess active ingredient (APAP) in the formulation. Liver failure is the primary adverse event from APAP overdose in adults. However, a study in laboratory animals in the 1980s demonstrated that the liver is not susceptible to APAP-mediated injury in very young animals, even with lethal doses of APAP [117]. |
21. Ultra-Orthodox Jews [118] in Israel have a reported prevalence of ASD less than half of that of reform Jews. Traditional circumcision practices employed by Ultra-Orthodox Jews do not utilize APAP. | Circumcision is often performed using APAP as an analgesic despite the fact that such use is of highly questionable effectiveness [113]. Almost all Israeli Jews are circumcised [119]. |
22. APAP is not used in domestic cats because they lack of a robust glucuronidation-dependent capacity for metabolism [120,121,122,123], making them susceptible to APAP-mediated injury. Human neonates also lack a robust glucuronidation-dependent pathway [124,125]. | Based on liver function in human babies and children, APAP was incorrectly determined to be safe for pediatric use in the 1960s and 1970s (see line of evidence # 4), before this evidence from veterinary science became available in the 1980s. One study in laboratory animals in the 1980s showed that even lethal doses of APAP do not cause liver failure in neonates [117], but the first study showing APAP-mediated neurodevelopmental brain injury in laboratory animals was not published until 2013 [59]. |
23. Surveys show that up to 50% of parents who have a child with ASD believe that their children’s ASD was induced by a vaccine [126,127]. | Although this belief has been widely attributed to a 1998 report describing 12 patients [128], the title of that report is not intelligible to individuals outside of the medical profession, and medical papers have seldom affected public opinion. A more likely explanation involves the induction of ASD by APAP use concurrent with vaccination, as suggested by Schultz [16,129]. |
24. Studies in several countries with chronic shortages of medication found dramatically lower-than-expected levels of ASD relative to other developmental issues, including Down syndrome. Reviewed by Jones et al. [4] | Not included in the previous review of this issue [4] is the apparently low levels of ASD in Cuba, where 241 cases of ASD in the entire nation (1 in 25,000 children) have been identified based on a 2016 report [130]. APAP is available in Cuba by prescription only [131], and multiple travel advisors cite APAP in particular as being in short supply in Cuba [132,133,134,135]. |
25. APAP binds directly to arachidonic acid [13] and affects arachidonic acid metabolism [12]. Alterations of arachidonic acid [15] and enzymes involved in arachidonic acid metabolism [14] are associated with ASD. | It is unknown what role arachidonic acid plays in ASD, but arachidonic acid plays a role in both the analgesic and antipyretic properties of APAP, and its metabolism is associated with ASD. |
26. The “missing heritability” paradox of ASD suggests that epigenetic factors or very early exposure to environmental factors might influence the onset of ASD [136]. | The role of APAP in the induction of ASD nicely resolves the missing heritability paradox connected with ASD, in which sibling studies indicate a high contribution of genetics, but genome wide studies fail to identify the genes involved [136]. The observation that abuse of a mother when she was a child is associated with ASD in the offspring [137] is one example of evidence that supports this view. |
27. ASD and fetal alcohol spectrum disorder (FASD) are similar in many regards. Reviewed by Jones et al. [4] A spectrum disorder can also be triggered by the drug valproate [5]. | These observations demonstrates that a complex spectrum disorder (FASD) sharing many similarities with ASD can (a) be induced by a single chemical and (b) be influenced by a variety of genetic and environmental factors. |
Variable | HR (CI) | p |
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APAP, actual risk built into virtual construct | 2.667 (NA) | NA |
APAP, result of regression analysis | 2.55 (2.41-2.71) | 2 x 10-16 |
APAP, adjusted for all contributing cofactors | 0.85 (0.80-0.90) | 2 x 10-7 |
OS factor 1, all individuals | 1.24 (1.23-1.26) | 2 x 10-16 |
OS factor 1, virtual individuals with APAP use only | 1.32 (1.30-1.34) | 2 x 10-16 |
OS factor 1, virtual individuals with no APAP use only | 1.00 (0.97-1.03) | 0.90 |
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