The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits
Abstract
:1. Introduction
2. Evidence Supports Extensive Influence of Acetaminophen Exposure on Current Rates of ASD
3. Alternative Hypotheses
4. Periods of Sensitivity to Acetaminophen during Neurodevelopment
5. Improper Use of Acetaminophen to Treat Fevers Is Common
6. Overdoses of Acetaminophen in the Pediatric Population
7. Misguided but Currently Accepted Use of Acetaminophen
8. Changes in Practice Need to Be Made
- Category 1:
- Administration of acetaminophen in a manner that was never intended should be discontinued. This includes treatment of temperatures that do not technically constitute a fever and administration of the drug more frequently and at higher doses than recommended.
- Category 2:
- Administration of acetaminophen under conditions in which evidence demonstrates a lack of effectiveness should be discontinued. This includes the treatment of the pain of circumcision and perhaps the treatment of fevers to prevent febrile seizures.
- Category 3:
- Administration of acetaminophen under conditions in which no evidence demonstrates long-term benefits of treatment or in which evidence demonstrates a lack of long-term benefits should be discontinued. This includes the treatment of fevers and prophylactic treatments prior to labor and delivery.
- Category 4:
- Administration of acetaminophen that is no longer recommended by governing medical bodies should be discontinued. This includes the treatment of patients receiving vaccinations and will hopefully include many more reasons for administration in the future.
- Category 5:
- Administration of acetaminophen under conditions where evidence indicates that it is or may be beneficial should not be continued without disclosure of the drug’s long-term risks for neurodevelopment. All caregivers, including parents, should be made aware of evidence related to both benefits and risks so that they can make informed decisions.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Summary of Evidence | Nature of Evidence |
---|---|
1. Early life exposure to APAP at doses similar to or even less than doses received by human babies and children results in long-term, profound modification of brain function in both laboratory mice and rats [5,6,7,8,17], by definition a severe adverse event that should have precluded any clinical testing of APAP in babies and small children. | Multiple, independent laboratory animal studies demonstrate that APAP is not safe for neurodevelopment. |
2. In laboratory rats, APAP affects the developing male brain more than the female brain [8]. In laboratory mice, males are more susceptible to APAP-mediated liver injury than are females [18]. ASD is more prevalent in males than in females [19]. | Laboratory animal studies of APAP-mediated injury reflect the sex distribution of ASD in humans. |
3. APAP causes apoptosis-mediated death of cortical neurons in adult laboratory rats at concentrations lower than it causes liver failure [20]. Affected cortical neurons are implicated in ASD [21,22], and individuals with ASD have increased levels of biomarkers for neuronal apoptosis [23,24,25]. | A laboratory animal study of APAP-mediated brain injury reflects biomarkers of injury in humans with ASD. |
4. Adult cats are susceptible to APAP-mediated injury due to the lack of a robust glucuronidation-dependent capacity for metabolism [26,27,28,29]. Human neonates similarly lack a robust glucuronidation-dependent pathway [30,31]. | Metabolic status causing sensitivity to APAP-mediated injury in an animal model reflects the metabolic status of human neonates. |
5. APAP use in babies and children was assumed to be safe during the 1970s despite the fact that it targets brain function and was never shown to be safe for neurodevelopment [32]. | Demonstration that the current safeguards for drug approval were bypassed for pediatric use of APAP. |
6. Circumcision of males, often performed using APAP as an analgesic, is associated with a twofold increase in the risk for early-onset (infantile) ASD [11]. | Temporal association with neonatal APAP use and ASD. |
7. APAP-containing products used by South Korean children were repeatedly found to contain amounts of the drug, exceeding the package label [33], and an exceptionally high prevalence of ASD was identified in South Korea [34,35]. | Temporal association of accidental, excess APAP administration and ASD. |
8. The popularity of APAP use and the prevalence of ASD was substantially higher in Denmark than in Finland in the mid-2000s (Figure 1). | Geographic association between APAP use and ASD. |
9. Ultra-Orthodox Jews [36] and Arabs [36,37] in Israel have a reported prevalence of ASD less than half of that of other Israelis. Traditional circumcision practices employed by Ultra-Orthodox Jews do not utilize APAP, and circumcision practices in Arab communities take place outside of the neurodevelopmental window sensitive to ASD induction (Figure 2). | Temporal association between neonatal use of APAP and ASD. |
10. Analysis of 61,430 babies in the Danish National Birth Cohort found an odds ratio (OR) of 1.3 (CI 1.02–1.66) for ASD associated with postnatal APAP exposure [13]. The approach used in the analysis is expected to dramatically underestimate the real odds ratio [1]. | Association with postpartum APAP use and ASD from one epidemiologic study. |
11. The ratio of regressive to infantile ASD rose at the same time as pediatric APAP use rose [14] after aspirin was associated with Reye’s syndrome [9]. | Temporal association between the pediatric use of APAP and the qualitative nature of ASD. |
12. 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 [9]. | Temporal association between pediatric use of APAP and the prevalence of ASD in the early 1980s. |
13. The incidence of ASD has steadily increased [9] as direct-to-consumer advertising [38] and perhaps other factors have driven up the use of pharmaceutical products. | Temporal association between the use of APAP and the prevalence of ASD post-1990. |
14. Maternal use of APAP during pregnancy is associated with long-term effects that include lower IQ, increased ASD, and increased ADHD in their children [12,13,39,40,41,42,43,44,45,46,47,48,49,50]. | Association with prepartum APAP use and neurodevelopmental problems from numerous epidemiologic studies, some with controls for indication. |
15. Levels of APAP in cord blood are associated with ASD [43]. | Association with APAP use during the peripartum period and the prevalence of ASD. |
16. APAP given alongside the MMR vaccine but not the MMR vaccination alone was associated with ASD [10]. | Dramatically enhanced risk of ASD associated with the use of APAP with vaccination found in a case-controlled study involving 81 children with ASD. |
17. APAP use during early childhood is associated with a dramatic increase in regressive ASD [10]. | Dramatically enhanced risk of regressive ASD associated with APAP use found in a case-controlled study involving 81 children with ASD. |
18. Many parents believe that their children’s ASD was induced by a vaccine [51,52]. APAP is frequently used with vaccinations, although vaccinations alone do not cause ASD. | Association between APAP use and ASD inadvertently and consistently made by a substantial fraction of parents of children with ASD. |
19. APAP use in adults temporarily blunts social trust [53] and awareness [54], emotional responses to external stimuli [55], and the ability to identify errors [56], indicating that the drug targets regions of the brain affected in patients with ASD. | The transient effects of APAP in adult humans are reflected in the symptoms of ASD. |
20. Cystic fibrosis is associated with unusually efficient (effective) metabolism of APAP [57,58], and evidence suggests that the prevalence of ASD is very low in patients with cystic fibrosis [9]. | Resistance to APAP-mediated injury is apparently associated with a very low prevalence of ASD. |
21. Genetic and immune factors associated with an increased risk of ASD have a detrimental effect on the body’s ability to metabolize APAP [9,59,60]. | Plausible mechanism: risk factors for ASD and for adverse reactions to APAP are equivalent. |
22. APAP is known to be highly toxic in the presence of oxidative stress [61] via a mechanism that involves the formation of the toxic metabolite NAPQI [62,63,64] and concomitant mitochondrial damage [65]. Oxidative stress [9] and possibly mitochondrial dysfunction [66] also play a role in ASD. | Plausible mechanism: production of toxic metabolites from APAP under conditions involved with ASD pathology is established. |
Time Period (Age) | Crude Estimates of Relative Fraction of Total ASD Induced by APAP | Source of Data/Information for Crude Estimate |
---|---|---|
Prenatal | 10–20% | Cohort studies |
Early postnatal period (birth to 5 days) | 50–60% | Association of ASD with cord blood acetaminophen [43], supported by association of ASD with circumcision [11] |
5 days until 2–12 months (regression not observable) | No information available | Not applicable |
2–12 months until 4 or 5 years (regression observable) | 20–30% | Small case control study [10], supported by observations of parents [51,52] |
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Parker, W.; Anderson, L.G.; Jones, J.P.; Anderson, R.; Williamson, L.; Bono-Lunn, D.; Konsoula, Z. The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits. Children 2024, 11, 44. https://doi.org/10.3390/children11010044
Parker W, Anderson LG, Jones JP, Anderson R, Williamson L, Bono-Lunn D, Konsoula Z. The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits. Children. 2024; 11(1):44. https://doi.org/10.3390/children11010044
Chicago/Turabian StyleParker, William, Lauren G. Anderson, John P. Jones, Rachel Anderson, Lauren Williamson, Dillan Bono-Lunn, and Zacharoula Konsoula. 2024. "The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits" Children 11, no. 1: 44. https://doi.org/10.3390/children11010044