Paracetamol (acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: a systematic review with citation tracking

Abstract

Although widely believed by pediatricians and parents to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Furthermore, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Publications on PubMed between 1974 and 2017 that contained the keywords “infant” and either “paracetamol” or “acetaminophen” were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. From these 218, a total of 103 papers were identified as sources of authority for the safety claim. Conclusion: A total of 52 papers contained actual experiments designed to test safety, and had a median follow-up time of 48 h. None monitored neurodevelopment. Furthermore, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed. What is Known:• Paracetamol (acetaminophen) is widely thought by pediatricians and parents to be safe when used as directed in the pediatric population, and is the most widely used drug in that population, with more than 90% of children exposed to the drug in some reports.• Paracetamol is known to cause liver damage in adults under conditions of oxidative stress or when used in excess, but increasing evidence from studies in humans and in laboratory animals indicates that the target organ for paracetamol toxicity during early development is the brain, not the liver. What is New:• This study finds hundreds of published reports in the medical literature asserting that paracetamol is safe when used as directed, providing a foundation for the widespread belief that the drug is safe.• This study shows that paracetamol was proven to be safe by approximately 50 short-term studies demonstrating the drug’s safety for the pediatric liver, but the drug was never shown to be safe for neurodevelopment. Graphical abstract Paracetamol is widely believed to be safe for infants and children when used as directed, despite mounting evidence in humans and in laboratory animals indicating that the drug is not safe for neurodevelopment. An exhaustive search of published work cited for safe use of paracetamol in the pediatric population revealed 52 experimental studies pointing toward safety, but the median follow-up time was only 48 h, and neurodevelopment was never assessed.

Acetaminophen Causes Neurodevelopmental Injury in Susceptible Babies and Children: No Valid Rationale for Controversy

“…As previously discussed, other factors impede the usefulness of such analyses, including the need for long term monitoring of exposures from the time of conception, an inability to separate confounding factors from oxidative stress-inducing cofactors, and the use of intravenous formulations of acetaminophen containing the antidote for acetaminophen toxicity in some studies. Indeed, an evaluation of the effect of early life exposure to acetaminophen on neurodevelopment outcomes would require a substantial effort that is unlikely to occur in the near future, as previously discussed (3).…”

“…A recent, exhaustive review of the literature, compete with citation tracking, demonstrated that, within the medical profession, acetaminophen is widely assumed to be safe when use as directed in the pediatric population (3). Unfortunately, the widely held belief that the drug is safe for pediatric use is based on numerous clinical studies that assume the liver will be the target of the drug's toxicity (3). Indeed, in adults, the liver was found to be the target of acetaminophen toxicity during the 1960s (4)(5)(6).…”

“…Indeed, in adults, the liver was found to be the target of acetaminophen toxicity during the 1960s (4)(5)(6). At that time, however, the view that babies metabolize drugs in a manner identical to adults was already known to be a dangerous assumption (7); this knowledge has yet to be applied to the toxicity of acetaminophen in human children (3). More than a decade later, a study using laboratory animals demonstrated that this assumption should not be applied to the metabolism of acetaminophen (8).…”

Antipyretic drugs: benefits and undesirable consequences

“…Препарат входит в клиниче- На сегодняшний день проведено примерно 50 исследований, демонстрирующих эффективность и безопасность парацетамола при лихорадках у детей. Однако эти исследования проводились с целью оценки гепатотоксичности, и медиана времени наблюдения составляла всего 48 ч. В настоящее время большой интерес представляет влияние препарата на состояние центральной нервной системы (ЦНС) [26].…”

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis- An Overview

“…It is noteworthy to note that long-term usage of glucocorticosteroids for a range of illnesses has no effect on the frequency of SJS/TEN incidence for the pharmaceuticals in question, but it seems that glucocorticoids increases the period between the commencement of drug consumption and the onset of SJS/TEN [47]. According to recent study on pediatric TEN, children may be more sensitive to acetaminophen than adults are and similar medications to those used in adults are being employed [48]. Rare cases of photo-induced TEN or SJS have been documented.…”