2022- The safety of pediatric use of paracetamol (acetaminophen): a narrative review of direct and indirect evidence

Journal: Minerva Pediatrics, July 2022; Full Article Here

Who are the authors?

  • Dr. William Parker, senior author on the study, with more than 35 years of research experience, mostly at Duke University Medical Center.
  • Dr. John P. Jones, a clinical pharmacologist with more than 18 years of experience in nonclinical, drug metabolism and pharmacokinetics, and translational research.
  • Dr. Zacharoula Konsoula, a PhD in pharmacology and toxicology with more than 15 years of experience in the pharmaceutical industry, including drug risk identification and mitigation.
  • Dr. Lauren G. Anderson, Director of Research Development for the Department of Surgery at Duke University Medical Center.
  • Dr. Maragatha Kuchibhatla, Professor of Biostatistics & Bioinformatics at Duke University.
  • Dr. Dillan Bono-Lunn, Assistant Professor at Elon University in the Department of Political Science and Policy Studies.
  • Dr. Kathryn J. Reissner, Associate Professor in the Behavioral and Integrative Neuroscience Program within the Department of Psychology and Neuroscience at UNC Chapel Hill
  • Five students working at Duke University also co-authored the paper. The students are Esha Patel, Antara Palkar, Jasmine Cendejas Hernandez, Joshua T. Sarafian, and Victoria G. Lawton.

Are there A.K.A.s to be aware of?

Acetaminophen, known as paracetamol in some areas outside of the USA, is commonly known in the USA by the brand names Tylenol, Little Fevers Children’s Fever/Pain Reliever, Little Fevers Infant Fever/Pain Reliever, and PediaCare Single Dose Acetaminophen Fever Reducer/Pain Reliever. Other drugs not mentioned here also contain acetaminophen, and the drug is known by other names outside the USA, including Calpol and Panadol.

Why was this study/article written?

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The drug is often self-delivered, delivered too frequently, and administrations are often overdoses; it is frequently given to treat low fevers that don’t necessitate the drug; the drug was deemed safe in babies and children because it did not cause liver damage in babies in children. However, no studies were ever conducted that showed the drug to be safe for neurodevelopment. The authors wish to assess and bring attention to evidence indicating that the drug carries risks for neurodevelopment in children.

What is the article about?

Short Summary

Overall, the article compiles various lines of evidence probing the safety of acetaminophen for neurodevelopment. The article takes into account the view that the body’s ability to tolerate acetaminophen is profoundly impaired by a condition called “oxidative stress.” As the authors point out, a wide range of factors, including antibiotic use, infections, and exposure to pesticides, exposure to plastic-derived toxins, genetics, and even skipping meals, can unfortunately cause oxidative stress. The relation between acetaminophen, oxidative stress, and autism markers is discussed.

Long Summary

1. Laboratory animal studies: the authors note that levels of toxic compounds are generally tolerated slightly better by laboratory animals than humans, leading to the conclusion that animal studies tend to underestimate the risks of drugs on humans; the drug was deemed ‘safe’ because it didn’t damage the liver in rats, however, the drug itself doesn’t work on the liver, it works on the brain, and even lethal doses delivered to rats didn’t damage the liver. A Swedish study was cited in which mice were exposed to the drug shortly after birth and could not learn a maze later in life; a Duke University study is cited in which rats who were exposed to the drug shortly after birth had 38% more asocial behavior than the control group, and in this same study, delivering oxidative stressors to the rats such as mock infections and antibiotics increased the asocial behavior to 51%; the diets of the rats/mice in these studies are receiving the equivalent of more than a dozen multivitamins a day, which can yield a higher ‘bar’ to reach oxidative stress; the authors also note that industrial standards for drug development do not screen for decrease in socialization or intelligence, and only screen for seizures, paralysis, and drowsiness; thus, the authors conclude that rat studies on acetaminophen underestimate the potential dangers in at-risk babies and children.

2. Human studies: a study by researchers at UCSD and SDSU is cited whose findings indicate a 6-fold risk of autism in one to five year old children “when vaccines were accompanied with acetaminophen, but not when the vaccines were given with ibuprofen.” The authors do note that the study was criticized, however, they state that a careful analysis of the study indicates its design was valid. A later meta-analysis of the long term effects of postnatal acetaminophen, which included 6 databases, 61,000 births which contained data on the occurrence of autism, revealed an increased 30% chance for autism associated with postnatal acetaminophen between birth and 18 months, and that this is not considering that mothers probably were underreporting giving their children the drug, as well as that the study didn’t consider exposure after 18 months. The authors point out that, if the 30% increase is correct, and if acetaminophen use in sick babies and children approaches 100%, then an astounding 23% of all cases of autism would be induced by acetaminophen, again not counting exposure after 18 months or in utero. At the same time, the authors created a simulated (artificial) population on a computer, and showed that common use of acetaminophen will cause a dramatic underestimation of the impact of the drug on the incidence of autism.

3. Acetaminophen ‘safe’ study: a study is reviewed about acetaminophen in which the authors of that particular study technically did not claim the drug was safe, but rather that further studies should be done to examine its effect on autism and ADHD. Additionally, the IV acetaminophen preparation used in the study contained an ‘antidote’ for excess formation of acetaminophen’s toxic metabolite, an antidote that is not present in any oral formulations given to most children. Finally, the study examined the exposure to acetaminophen within a window of only 4 days. The authors end the section by indicating that even with the antidote, acetaminophen exposure in rats still resulted in increases in asocial behavior.

4. Circumstantial Evidence: autism began to rise in the 80s, which coincides with the rise in use of acetaminophen. The pediatric community switched from aspirin to acetaminophen, which also coincides with a shift in autism from less infantile autism to more regressive autism. Autism continued to rise in the 90s and 2000s, as drug advertising increased. The authors indicate that while association cannot prove causation, causation itself cannot occur without association, and multiple associations in the absence of viable alternative explanations and in the face of significant direct evidence are very damning.

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5. Additional studies: a study on Vietnamese children found autism higher in children of farmers compared to the children of government administrators, pointing out that the liberal use of pesticides, which causes oxidative stress, and is very likely the autism-inducing factor in the farming community. Another study found the prevalence of autism is 50% more in circumcised boys, apparently due to acetaminophen exposure at the time of the procedure. Here the authors point out that, based on circumcision rates in a population such as the U.S.A., induction of autism by acetaminophen exposure at the time of circumcision could account for an astounding 17% of all cases of autism.

6. Alternative explanations: the authors explain how several alternative ideas are readily falsifiable. For example, the authors undermine the argument that there is no substantial increase in autism over the past 40 years. They debunk the idea that autism is caused by the reasons for taking acetaminophen without involvement of the drug itself. They also explain how the presence of biomarkers for oxidative stress at birth does not mean that babies are born with autism. Further, they point out that the assertion that one drug cannot be responsible for different disorders such as autism and ADHD is not based on rational arguments or currently available evidence.

When was the data collected; or when did study take place?

The study is a review study published in 2022. The authors themselves did not collect data; but rather, analyzed other studies to form a collective analysis of what the current research shows.

Where did study take place; where was information gathered from?

Evidence from previously conducted laboratory animal studies and human studies are used to conduct an analysis on the effect of acetaminophen on autism.

How did they analyze the data; how did they come to their conclusions?

Data from previous studies was reviewed. Additionally, the authors created an artificial data set in which two thirds of autism was caused by acetaminophen and oxidative stress, and analyzed that data set using standard, multivariate analysis.

What was found; what were the correlations or causal links found?

The authors conclude that, although most babies and children are not apparently harmed by the drug, a subset of babies and children are at risk of acetaminophen-induced neurological injury because of oxidative stress. The authors conclude “without any reasonable doubt” that many if not most cases of autism spectrum disorder (autism) are caused by exposure of at-risk children to acetaminophen between birth and age 5 years. They further conclude that, in the face of widespread use of acetaminophen, any factor that causes oxidative stress will be associated with autism.

They also warn against a ‘consensus bias,’ which is accepting the drug simply because others accept it and use it. A final source of resistance the authors note is the resistance from the medical industry itself, due to careers and reputations being damaged by a situation in which individuals have shown support for a drug that actually causes autism, which can lead go conflict of interest that would affect their judgement.

What do the authors suggest people do with the information?

The authors suggest future research on acetaminophen’s effect on neurodevelopment and predict the following experimental outcomes: that paracetamol induced toxicity in lab rats exposed between birth and 10 days will be observed in the nervous system; that non-lethal but severe acetaminophen induced toxicity in lab rats will be characterized by profound impairment of social interactions (similar to autism); and that a reduction of postnatal use of acetaminophen in at risk babies and children will result in lower autism rates.

The authors conclude the article by stating that the evidence reviewed is cause for concern, physicians and the public should be notified of this evidence, and the severity of this issue necessitates immediate resolution.

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