Paracetamol (Acetaminophen) Use in Infants and Children Was Never Shown to Be Safe for Neurodevelopment: A Systematic Review

Background: Although widely believed 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. Further, 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. Methods: 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 identi�ed that made claims that paracetamol was safe for use with infants or children. Of these, a total of 103 papers were identi�ed as sources of authority for the safety claim, and 36 of those contained actual experiments designed to test safety. Results and Conclusions: The 36 experiments described had a median follow-up time of 24 hours, and none monitored neurodevelopment. Further, 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 su�cient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed.


Background
Hundreds of reports claim emphatically that, when used as directed, paracetamol (acetaminophen) is safe for use in babies and in children.However, mounting evidence points toward the view that paracetamol exposure during early development can have an adverse effect on neurodevelopment, even when used as directed.For example, in a recent review [1], eight studies supporting a link between prenatal paracetamol exposure and neurodevelopmental problems were identi ed [2][3][4][5][6][7][8][9].In the three years since that review, ve additional studies have con rmed this same relationship, three of which have used data from the Norwegian Mother and Child Cohort Study [10][11][12][13][14].Although exposure to paracetamol in utero is associated with neurodevelopmental problems, even after consideration of potentially confounding factors, the effects are typically small and the amount of paracetamol required to yield the effect is greater than the amount typically used by average individuals.For example, after adjusting for potential confounders such as parental education level, use of vitamin supplements, parental BMI, smoking, and use of other drugs, Skovlund and colleagues found a weak yet signi cant association between prenatal exposure to paracetamol and mother-reported communication skills: the chances of being in a lower development category increased with increasing periods of prenatal paracetamol use but not prenatal opioid use [10].In another example, using propensity score matching, Vlenterie and colleagues found that 28 or more days of paracetamol use during pregnancy was associated with a modestly increased risk of delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70)by children at 18 months [11].
Evidence points toward a higher risk of paracetamol-induced neurodevelopmental disorders when exposure occurs after birth as compared to in utero.Studies using laboratory rodents demonstrate that exposure to near therapeutic doses of paracetamol during the rst days of life induces profound, longterm neurological changes [15,16], whereas somewhat higher doses are required to induce permanent neurological damage during pregnancy [17].These laboratory studies demonstrate that the target organ for toxicity in neonates is the central nervous system, not the liver, and demonstrate that if paracetamol had been tested using current guidelines, it would never have been approved for use in children.More concerning are observations in children indicating that paracetamol is not safe for neurodevelopment.
The 2008 study which rst raised a red ag regarding the safety of paracetamol during neurodevelopment found a greater than 20-fold risk of regressive autism with paracetamol use during childhood [18].Although this relatively small study did not attract enough interest to promote larger studies, other lines of evidence support the view that paracetamol exposure during early life can lead to neurodevelopmental disorders.For example, a startling 2-fold greater incidence of infantile autism in circumcised boys compared to non-circumcised boys [19] can be readily explained by potentially negative impacts of paracetamol exposure during and following the circumcision procedure [1].Sadly, the widely held and entrenched belief that vaccines induce autism [20,21] may be yet another result of the impact of paracetamol on neurodevelopment in combination with widespread use of the drug during vaccination [1].
With the above concerns in mind, a systematic evaluation of the peer-reviewed literature was initiated to address the question of why paracetamol is widely believed to be safe for use during early development.
All papers published between 1974 and 2017 that contained the keywords "infant" and either "paracetamol" or "acetaminophen" were considered.All papers which made claims that paracetamol or acetaminophen is safe for use in infants or children were identi ed, and the justi cation for this claim was critically evaluated.

Methods
As a rst step in understanding why paracetamol is thought to be safe during early development, all titles and abstracts in the PubMed® Database with keywords "infant" and "acetaminophen or paracetamol" published between 1974 and 2017 were identi ed.The term "infant" rather than "child" was selected because (a) the number of papers with the term "child" was prohibitively large, and (b) the focus of the study was intended to be on drug exposure during early development, from birth to age approximately 6 years, not individuals up to the age of 17 years.In all cases, the terms paracetamol and acetaminophen were taken to be synonymous, and no distinctions were made.
In the second step, two coauthors (JCH and JTS) independently screened all titles and abstracts.In this step, articles that could not be obtained in English and all articles not describing use of paracetamol in humans were eliminated from the study.Based on titles and abstracts (if available), articles were tagged which were deemed likely to make claims regarding the safety of acetaminophen use in infants and children between birth and age 6 years.
In the third step, two coauthors (JCH and JTS), continuing to work independently, examined full texts of all tagged titles and abstracts.Texts were examined for the following three assertions: (a) paracetamol use is "safe" in children or infants (b) paracetamol is the "drug of choice" in children or infants (c) paracetamol use is "recommended" for children or infants In cases where the terms "drug of choice" or "recommended" were used, the context was considered.In some cases, particularly in manuscripts expressing caution regarding the use of paracetamol, these terms were not taken to imply safety, but rather were taken to be an indicator of the common acceptance of the drug.These articles were excluded from the study.Based on this approach, articles were tagged that were considered to have made safely claims regarding the use of paracetamol in infants or children younger than 6 years old.
Still working independently, two coauthors (JCH and JTS) evaluated each manuscript making a claim of safety, determining the source of authority for the stated claim.If no literature was cited to support the claim, this was documented.In cases where the source that was cited contained another citation, that secondary reference was obtained and evaluated.This process continued as needed until an original source or sources describing an actual demonstration of safety was identi ed.An example of the results of this process is shown in Fig. 1.

Table 1
Number of citations identi ed in the systematic search during each step of the study.Numbers are provided for both analysts performing the work (JCH and JTS).The overlap is the number of citations that were the same between the two analysts.*Numbers in parentheses indicated the number of citations in which both analysts identi ed the same citation, but not the same source or sources as the authority for claims of safety.
Step JCH Overlap JTS Total In the fourth step, any discrepancies between the analyses provided by coauthors JCH and JTS were arbitrated by coauthor WP.In the fth step, articles upon which safety claims were based were compiled.Finally, articles upon which safety claims were based and which contained experiments designed to assess safety were evaluated.For each experiment described, the study group, endpoints measured, and follow-up time were evaluated.

Results
An overview of results from a systematic search for studies demonstrating safety of paracetamol use in infants and children is shown in Table 1.The initial Medline search provided 3096 articles that contained the terms infant and either paracetamol or acetaminophen that were published between 1974 and 2017.
From these articles, 467 were selected for assessment based on likelihood of safety claims regarding use of paracetamol in infants or children.Of these 467 articles, 218 made safety claims regarding the use of paracetamol in infants or children.During this phase of the study, numerous articles were identi ed which either claimed or demonstrated that paracetamol use, even at doses beyond the recommended dose, does not generally cause long-term liver damage in infants or children.Any claims of safety for liver function were not evaluated in detail and were not considered in this study.Only general claims of safety were assessed.
Of the 218 articles making claims that paracetamol use in infants or children is safe, half (114) provided no citation.The other half (114) of the articles cited additional articles as evidence that paracetamol is safe in infants or children.Cited articles were carefully evaluated as described in the methods.In some cases, those "primary" cited articles did not make original claims of safety, but rather cited additional ("secondary") articles.In cases where a primary article cited another article, the primary article was not considered to have made an original claim of safety, and was not evaluated further.An example of the results of this process is shown in Fig. 1.Both primary articles and secondary (and tertiary, etc) articles attributed with claims of the safety of paracetamol use in infants or children were compiled and are shown in Table 2.In total, 103 articles were identi ed which were cited as containing original claims that paracetamol use in infants or children is safe when used as directed.
Several studies emerged as popular citations for the claim that paracetamol use in infants or children is safe when used as directed.Only 19 articles were cited more than twice, and the most popular article [22] was cited a total of 13 times (Table 2) by the 218 articles we identi ed.However, in some cases, well cited articles did not make original claims of safety, and are therefore not included in Table 2.For example, an article by Perrott and colleagues in 2004 [23] was cited a total of 7 total times by the 218 articles we identi ed.However, Perrott's article, being a review, does not make original claims of safety, but rather cites additional articles as the authority for assurance of safety (Fig. 1).Thus, Perrott's article is not included in Table 2 as an original source for the claim that use of paracetamol is safe for infants and children when used as directed.
Of the 103 articles cited as authority for the safety of paracetamol use in infants or children, 27 did not make claims of safety and did not address safety experimentally (Table 2).Thus, 76 of the 103 articles did address safety, and 48 of these (63%) had already been identi ed in the original 218 articles culled from the Medline search.Of the 103 articles, 36 articles described experimental studies which involved paracetamol use in infants or children.Although several of these studies provided measures of liver function (Table 2), none of these 36 studies provided any assessment of neuropsychiatric function.
Further, the median follow-up time of all 36 studies was 24 hours (Fig. 2), far too short to identify any long-term effects of drug exposure on neuropsychiatric function.Four studies had a follow-up time of longer than 10 days, with one study in particular [24] evaluating patients out to one year.However, these studies were blind to any potential effects of drug exposure on long-term neuropsychiatric function.For example, although patients were followed for a full year in one study [24], the only endpoint measured was re-admission for surgery.
The path from more recent papers to the original research addressing the safety of paracetamol in infants and children was sometimes convoluted.In one notable case, a popular citation did not did appear the literature (Table 2).Not only did the volume and journal number not match, but the title could not be found elsewhere.As another example, the citations reporting safety of paracetamol use in children reported by Temple and colleagues in 2017 [25] are illustrated in Fig. 1.This article provides a detailed description of three prior reports to the European Medicines Agency (reports 24570, 24571, and 47402) which, together, according to the authors, "con rm that the recommended standard paracetamol dose of 10 to 15 mg/kg is a safe and effective dose for use in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours."However, the only safety measure used in the three studies was ALT levels as a marker for liver function, assessed for a maximum of 72 hours.In addition to the three reports described in their publication, Temple and colleagues cite 10 additional articles as sources for safety, including the claim that paracetamol has a "well-established e cacy and favorable safety pro le" (Fig. 1).Among these 10 papers is a clinical trial [26] that addresses e cacy but not safety, and refers to two other papers that address safety, one by Lesko [22].The paper by Lesko contradicts the view that paracetamol is safe, nding that paracetamol is signi cantly worse than ibuprofen in terms of risk for outpatient visits following treatment of children with asthma.Another of the articles cited by Temple in 2017, a review written by Temple more than 30 years before [27], cites a paper in the Federal Register [28] as the source for the statement that "Paracetamol is relatively free of side effects and has a wide margin of safety between therapeutic doses and toxic doses."The document in the Federal Register [28], a lengthy treatise primarily focused on determination of the appropriate dose for adults of salicylates in general and aspirin in particular, in turn cites two papers involving safety studies of paracetamol in the human pediatric population.One of those studies [29] evaluated 98 children using a blinded approach comparing aspirin and paracetamol, and monitored the children for only 6 hours.The other study [30] monitored 20 children following administration of both aspirin and paracetamol.In that study, monitoring occurred for 6 hours or less and no information was provided regarding particular side effects that were being assessed.Importantly, the Federal Register [28] attributed their view that paracetamol has "a wide range of safety" to laboratory animal studies showing that the lethal dose of paracetamol is signi cantly greater than the dose administered to humans.Unfortunately, studies had not been conducted at that time showing that paracetamol induces permanent neurodevelopmental injury in laboratory animals at far lower doses than the lethal dose [15,16], similar to doses administered to infants and children.

Discussion
Our initial search of the PubMed® Database and review of more than 3000 titles and abstracts yielded 218 papers making claims that paracetamol is safe for infants and children when used as directed.
Claims of safety in those 218 papers were traced back to 103 articles shown in Table 2, but less than 20 of those were cited more than twice, indicating that a limited number of studies are considered key or cornerstone to the view that paracetamol is safe for use in infants or children.
This study con rms the view that paracetamol use in infants and children is widely thought to be safe when used as directed, without reservations or caveats.The fact that 27 out of 103 citations did not, in fact, demonstrate safety or make safety claims might suggest that the safety of paracetamol is taken for granted, and is not carefully considered.This view is supported by the observation that one popular citation for safety does not exist in the literature.

Conclusions
Despite apparently being taken for granted, this study demonstrates that paracetamol was never shown to be safe for neurodevelopment.This conclusion is consistent with emerging studies showing a connection between paracetamol use during development and long term neuropsychiatric disfunction as described in the Introduction.This conclusion is also consistent with emerging studies in animal models showing exquisite sensitivity of long-term behavior to early life exposure to paracetamol at neartherapeutic doses.
Although not the intended purpose of this systematic review, it demonstrated that paracetamol has been proven safe for liver function in infants and in small children, even at doses higher than those currently recommended.During the course of this review, an assumption was repeatedly encountered: because the target of paracetamol toxicity in adults is the liver, demonstration of safety in infants and children need only be tested in the liver.This assumption was/is held despite the fact that the target tissue for drug function is in the central nervous system, not the liver.A similar assumption has proven tragically fatal in the past, when it was assumed that metabolism of the antibiotic chloramphenicol was the same in infants as in adults.In that case, administration of the drug in infants led to a number of deaths [31][32][33] before the problem was identi ed.

List Of Abbreviations
BMI, body mass index.

Declarations
Ethical Approval and Consent to participate: Not applicable Consent for publication: Not applicable.
Availability of supporting data: The dataset analyzed (PubMed®) is in the public domain.
Competing interests: The authors declare that they have no competing interests.
Funding: Not    Supplementary Files

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Table 2
Sources cited as stating that acetaminophen is safe for infants or children when used as directed.*This article is cited as "Renn E. The antipyretic use of paracetamol versus ibuprofen in a pediatric care setting.Physical Therapy.2000;25:395-397."This reference does not apparently exist: The volume number corresponding to the year 2000 for the journal Physical Therapy is 80, not 25.We were unable to determine what actual article it may have originally referred to.**The Canadian Pediatric Society paper from 1998 was mis-cited as being from 2000 in one instance.*** This article, cited as Kehlet and Werner (2003) from the journal Drugs, Volume 63, pp 15-22 (Spec no 2), does not exist on the journal's website for unknown reasons.