Acetaminophen causes neurodevelopmental injury in susceptible babies and children: no valid rationale for controversy

Abstract

Despite the worldwide acceptance of acetaminophen (APAP) as a necessary medicine in pediatrics, evidence that early exposure to APAP causes neurodevelopmental injury in susceptible babies and children has been mounting for over a decade. The evidence is diverse and includes extensive work with laboratory animals, otherwise unexplained associations, factors associated with APAP metabolism, and limited studies in humans. Although the evidence has reached an overwhelming level and was recently reviewed in detail, controversy persists. This narrative review evaluates some of that controversy. Evidence from the pre- and postpartum periods was considered to avoid controversy raised by consideration of only limited evidence of risks during the prepartum period. Among other issues, the association between APAP use and the prevalence of neurodevelopmental disorders was considered. A systematic review revealed that the use of APAP in the pediatric population was never tracked carefully; however, historical events that affected its use were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. Moreover, problems with the exclusive reliance on results of meta-analyses of large datasets with limited time frames of drug exposure were reviewed. Furthermore, the evidence of why some children are susceptible to APAPinduced neurodevelopmental injuries was examined. We concluded that available evidence demonstrates that early exposure to APAP causes neurodevelopmental injury in susceptible babies and small children.

Keywords: Acetaminophen; Autism; Neurodevelopment; Paracetamol.

Fig. 1.

Summary of evidence pointing toward the induction of neurodevelopmental disorders by early exposure to acetaminophen (APAP). The numbering of individual lines of evidence is as in Table 1. References and more detailed descriptions of each line of evidence are listed in Table 1. The 20 lines of evidence are separated into 5 miscellaneous lines of evidence, with the remaining 15 lines of evidence divided evenly into 5 categories: Studies in animal models, associations with human activities, associations in time, postnatal observations, and molecular mechanism of action. Lines of evidence numbers 10 and 11 were derived from the same data, while lines of evidence numbers 14 and 16 were derived from the same study. These lines of evidence are therefore not independent, which is indicated by the connecting lines in the diagram. DNBC, Danish National Birth Cohort; CF, cystic fibrosis.

Fig. 2.

Studies tracking acetaminophen (APAP) use in the general population ≤5 years of age. In diagram A, the systematic search strategy is shown. The initial search was conducted of PubMed on August 25, 2022 without any restrictions on time frame. The search terms used were (acetaminophen or paracetamol)+(use or administration)+(infant or child or postnatal or pediatric or neonate or newborn or baby)-(review or mouse or mice or rat). The initial title review was conducted by co-author WP. The initial full-text review was conducted by co-author LZ, while the second and final full-text review was conducted by co-authors LZ and WP. In diagram B, variations in studies probing the use of APAP in babies and children younger than 6 years of age is illustrated. Results are shown for all 5 countries in which at least 3 studies using independent data sets have evaluated the use of APAP in babies and children under 6 years of age. In cases in which 2 studies used the same data set, the results are presented together. The number of babies/children in the study, their ages at the time of the study, and the years in which APAP use was measured are shown in the box attached to each data point. The lowest value shown for the country of Spain is the average of 3 similar values (49.1%, 51.4%, and 52.0%) from three studies using the International Study of Asthma and Allergies in Childhood in Spain data, 2 evaluating data from 2000–2003 [116,117] and one evaluating data from 2006–2007 [118].

Fig. 3.

Temporal associations between the reported incidence of autism spectrum disorder (ASD) in California and factors affecting the use of acetaminophen (APAP). The prevalence of ASD in California as compiled by Nevison et al [35] is shown in the graph. The data are a composite of “snapshot” data (information collected at one point in time) from the California Department of Developmental Services (covering birth years 1970–2011) [35]. From 1982 to 1986, government warnings on using aspirin due to the association with Reye syndrome were issued from the Centers for Disease Control and Prevention and the Food and Drug Administration [119]. From 1990 to 2007, total spending on direct-to-consumer pharmaceutical advertising underwent great increases from $47 million to $5 billion [120]. In the inset, previously published survey data [28] from the Autism Research Institute and the Autism Society of America are shown [28]. The number of surveys that were collected within a given time frame are shown, and reports are separated into reports describing infantile (nonregressive or early-onset) ASD (solid line) and those describing regressive ASD (dashed line). The information in this diagram does not consider increases in use of glutathione-depleting compounds such as pesticides and plastic-associated chemicals that have occurred during the time frame shown. Given that oxidative stress is a co-factor in the induction of APAP-induced neurodevelopmental issues [2,3,41], such factors are expected to influence the incidence of ASD [41].

Fig. 4.

Metabolism of acetaminophen (APAP) in humans. The 3 pathways—glucuronidation, sulfation, and oxidation—followed by a reaction with glutathione are shown. The major pathway in babies and in children, sulfation, tends to be impaired in children with autism spectrum disorder (ASD). This is expected to shunt more of the drug through the oxidative pathway, resulting in the production of excess N-acetyl-p-benzoquinone imine (NAPQI), the toxic compound shown in the diagram. Unfortunately, children with ASD also tend to have a reduced ability to detoxify NAPQI, resulting in increased toxicity of APAP due to excess NAPQI.

Fig. 5.

Schematic diagram illustrating relative sensitivities of laboratory animal pups and of human infants and children to acetaminophen (APAP)-induced neurodevelopmental injury. The diagram illustrates how laboratory conditions can be modified to enhance oxidative stress, thus increasing the sensitivity of the animals to APAP-induced neurodevelopmental injury. The schematic diagram illustrates that the sensitivity of healthy laboratory pups to APAP-induced neurodevelopmental injury is relatively homogenous and less broadly distributed than that of human babies and children. Further, the diagram illustrates that the sensitivity of healthy laboratory animal pups to APAP-induced neurodevelopmental injury is of lesser magnitude than that of at-risk human babies and children. In this model, exposures of laboratory animals can be made comparable to exposures in at-risk human babies and children by either increasing the dose of APAP in the laboratory pups, or increasing oxidative stress in the laboratory pups. Quantitative estimates of the difference in the risks between laboratory animal pups and human babies and children have not been made, and the schematic diagram is not meant to indicate quantitative values.