Acetaminophen Use Linked to Autism Spectrum and Attention Deficit/Hyperactivity Disorders
Acetaminophen is one of the most commonly used drugs during pregnancy – used by more than 50 percent of expectant mothers in the U.S. Once widely thought to be safe for such use, recent studies suggest the opposite. Indeed, the overall body of scientific literature demonstrates a link between acetaminophen use during pregnancy and an increased risk of the development of Autism Spectrum Disorder (ASD) or Attention-Deficit/Hyperactivity Disorder (ADHD) in children. These studies suggest that the increase in ASD and ADHD in children over the past decades is not fully explained by changes in diagnoses or awareness. Instead, recent studies discuss the connection between acetaminophen use during pregnancy and the drug’s effect on fetal neurodevelopment.
There are numerous biological explanations for the effect acetaminophen can have on the developing brain. For example, acetaminophen has endocrine-disrupting properties and may interrupt the maternal hormone signaling that regulates the infant’s normal brain development. In addition, acetaminophen can cross the placenta and fetal blood-brain barrier, the two biologic mechanisms meant to protect the growing infant from toxins.
Despite this evidence, at no time have manufacturers of acetaminophen warned about this risk, and acetaminophen is not currently contraindicated for usage during pregnancy.
What is Acetaminophen?
Acetaminophen, also known as paracetamol, is both the generic name of common-brand-name Tylenol and the active ingredient in the many medications currently used to treat fever and mild- to-moderate pain. Harmon Northrop Morse created acetaminophen at Johns Hopkins University in the 1870s, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried it on humans.
The Food and Drug Administration (FDA) approved acetaminophen as a prescription drug in 1950, and it was made available for over-the-counter use in 1955. Originally marketed and sold to treat fever in children, Johnson & Johnson first introduced Tylenol for the adult population in 1961. By July 1976, it was the #1 analgesic (pain reliever) in the U.S.
What are ASD and ADHD?
Autism Spectrum Disorder is a condition related to brain development that affects how people interact with others, communicate, learn, and behave. People with ASD often have restricted or repetitive behaviors or interests. According to the CDC, approximately 1% of the world population has ASD – amounting to over 75,000,000 people or about 1 in 44 children. Just 22 years ago, the rate of ASD was 1 in 150 children. Only four of 10,000 people were diagnosed with ASD in 1980. Before that, the rate remained pretty consistent – 2 to 4 in 10,000 in the 1960s and 1970s.
After first being described by Leo Kanner, an Austrian-American psychiatrist and physician, as an innate disorder exhibiting an “obsessive desire for the maintenance of sameness,” autism spectrum disorder has undergone multiple definitions and diagnostic criteria. The view of ASD evolved as researchers discovered that autism is connected to brain development, and after it became understood that autism constitutes a spectrum of conditions rather than just one condition.
The American Psychiatric Association (APA) releases periodic Diagnostic and Statistic Manuals (DSMs) which categorize diseases to aid in properly diagnosing conditions. The APA’s view of autism has evolved over time.
The fourth edition of the DSM, which was released in 1994 and revised in 2000, was the first edition to categorize autism as a spectrum. This version listed five conditions with distinct features: autism, pervasive developmental disorder not otherwise specified (PDD-NOS), Asperger’s disorder, childhood disintegrative disorder (CDD), and Rett syndrome.
The criteria were updated in 2013, with the release of the 5th edition of the DSM. Instead of five separate conditions, one diagnosis – ASD – is used. To meet the diagnostic criteria for ASD, a child must have persistent deficits in each of three areas of social communication and interaction and at least two of four types of restricted, repetitive behaviors:
- Persistent deficits in social communication and social interaction, as manifested by the following, currently or by history:
- Deficits in social-emotional reciprocity, including from abnormal social approach and failure of normal conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.
- Deficits in nonverbal communication behaviors used for social interaction, including from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and using gestures; to a total lack of facial expressions and nonverbal communication.
- Deficits in developing, maintaining, and understanding relationships, including from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.
- Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following:
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- Stereotyped or repetitive motor movements, use of objects, or speech.
- Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior.
- Highly restricted, fixated interests that are abnormal in intensity or focus.
- Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of the environment.
Additional criteria include:
- Symptoms must be present in the early developmental period even though they may not become fully manifest until social demands exceed limited capacities or may be masked by learned strategies in later life.
- Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
- Intellectual disability or global developmental delay do not better explain symptoms.
There are three functional levels of ASD requiring varying levels of support with activities of daily living. Treatments for ASD include behavioral management therapy, cognitive behavior therapy, joint attention therapies, medications, occupational therapy, physical therapy, social skill training, and speech-language therapy. Treatment for ASD lasts a lifetime, as there is no cure.
ADHD, a chronic condition that affects millions of children and often continues into adulthood, is one of the most common neurodevelopmental disorders. ADHD was first noted in 1902 by Sir George Frederic Still, a British pediatrician, and, like autism, the definition has changed over time. Originally called “hyperkinetic reaction of childhood,” it was first formally recognized by the APA as a mental disorder in the 1960s. In the DSM-III, ADHD became known as attention deficit disorder (ADD) with hyperactivity and without hyperactivity. The revised DSM-III removed the distinction between the two, and the condition is now diagnosed as ADHD. Currently, the three symptoms of ADHD are inattentiveness, impulsivity, and hyperactivity, with three subtypes: combined type ADHD, predominantly inattentive type ADHD, and predominantly hyperactive-impulsive type ADHD.
Many people experience some inattention, unfocused motor activity, and impulsivity, but for people with ADHD, these behaviors are more severe, occur more often, and interfere with how they function socially, at school, or in a job. ADHD begins in childhood and continues through adulthood. ADHD contributes to low self-esteem, troubled relationships, and difficulty with school and work. Diagnosing a child with ADHD is a process with several steps; there is no single test. Treatments include medication, education, skills training, and psychological counseling, or a combination of these. As with ASD, there is no cure for ADHD.
What are the studies?
One of the most recent studies, published in the European Journal of Epidemiology in May 2021, found that children prenatally exposed to acetaminophen were 19% more likely to have borderline or clinical ASD and 21% were more likely to have borderline or clinical ADHD symptoms.
In September 2020, JAMA Pediatric published a birth cohort study that found that ADHD and related brain phenotypes were associated with prenatal exposure to acetaminophen, also known as APAP.
But, prior to these studies, a growing body of evidence had already established a link. A 2018 review of nine publications reporting associations between APAP use and neurodevelopmental outcomes found that all studies included in the review suggested an increased risk of neurodevelopmental outcomes following exposure and that pregnant women should be cautioned against indiscriminate use of acetaminophen.
To date, the studies performed have been observational. Observational studies are studies that observe what happens naturally and record results. Usually, researchers conduct observational studies when it is difficult, impossible, or unethical to assign study participants to experimental groups randomly.
The APAP observational studies include both cohort studies and case-control studies.
A cohort study involves identification of subjects at a point in time when they do not have the condition being studied, then compares the incidence of the condition among groups of exposed and unexposed (or less-exposed) subjects. Cohorts, or individuals being studied, may be identified retrospectively or prospectively. Either way, the condition status is established at least twice: it must be established that a cohort did not have the condition at the beginning of the observation period, and the cohort is examined again to determine whether or not the condition subsequently developed.
A case control study is a study that compares two groups of people: (1) those with the condition under study (cases) and (2) a similar group of people who do not have the condition (controls). Researchers study the medical and lifestyle histories of the people in each group to learn what factors may be associated with the condition. For example, as is relevant here, one group may have been exposed to a particular substance that the other was not. These studies are retrospective. Where the cohort study is concerned with frequency of disease in exposed and non-exposed individuals, the case-control study is concerned with the frequency and amount of exposure in subjects with a specific disease (cases) and people without the disease (controls).
The following is a summary of the studies released to date:
Schultz, S., et al. (2008). Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder. SAGE Publications.
This case-control study focused on whether APAP use after measles vaccine is associated with autistic disorder. The case participants were parents of children with autistic disorder, the controls were parents of children without autistic disorder.
Conclusion: APAP use after measles vaccine was associated with autistic disorder.
Authors: Dr. Stephen T. Schultz; Dr. Hillary S. Klonoff-Cohen, PhD in epidemiology; Deborah L. Wingard; Natacha A. Akshoomoff, PhD in clinical psychology and neuropsychology; Caroline A. Macera; and Ming Ji.
Brandlistuen, R.E., et al. (2013). Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. International Journal of Epidemiology.
This was a prospective cohort study performed between 1999 and 2008 as a subproject of the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, which used a sibling-control analysis to separate the effect of genetic confounding from the effect of the medication. The study examined potential associations between prenatal exposure to acetaminophen and certain psychomotor, behavioral, and temperament outcomes in children.
Conclusion: Children exposed to long-term use of paracetamol during pregnancy had substantially adverse developmental outcomes at 3 years of age.
Authors: Ragnhild Eek Brandlistuen, Eivind Ystrom, Irena Nulman, Gideon Koren, and Hedvig Nordeng
Liew, Z., et al. (2014). Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatric.
This prospective cohort studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort (DNBC). The DNBC aimed to study causes of pregnancy complications and diseases in children, with a focus on adverse effects of medications and infections. The authors of this article used the DNBC to evaluate the risk for developing ADHD-like behaviors, receiving a diagnosis of hyperkinetic disorder, or using ADHD medications, after fetal exposure to acetaminophen.
Conclusion: Prenatal use associated with higher risk for HKDs and ADHD-like behaviors.
Authors: Zeyan Liew, MPH; Beate Ritz, MD, PhD; Cristina Rebordosa, MD, PhD; Pei-Chen Lee, PhD; and Jorn Olsen, MD, PhD.
Liew, Z., et al. (2015). Maternal Use of Acetaminophen during Pregnancy and Risk of Autism Spectrum Disorders in Childhood: A Danish National Birth Cohort Study. Autism Research.
This study also used the DNBC, but, here, the authors investigated whether prenatal acetaminophen use increased the risk of ASD in children. Prenatal use of acetaminophen was assessed by phone interviews with mothers who were screened for whether they took any painkillers during their previous pregnancy, and if they answered yes, were asked to report use on a week-by-week basis. This was to provide information on trimester and duration of use. ASD diagnoses were obtained by linking the DNBC to the Danish National Hospital Registry which contains records for certain types of admissions and the Danish Psychiatric Central Registry which tracks admissions to psychiatric hospitals.
Conclusion: Prenatal exposure to acetaminophen associated with elevated risk for ASD with hyperkinetic features
Authors: Zeyan Liew, MPH; Beate Ritz, MD, PhD; Jasveer Virk; Pei-Chen Lee, PhD; and Jorn Olsen, MD, PhD.
Avella-Garcia, C.B., et al. (2016). Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. International Journal of Epidemiology.
This Spanish birth cohort study included 2,644 mother-child pairs recruited during pregnancy. Use of APAP was evaluated prospectively in two structured interviews, once at 12 weeks and once at 32 weeks of pregnancy, determining whether the mothers ever or never used acetaminophen during their pregnancy, and if used, whether sporadically or persistently based on defined measures. Children’s neurodevelopmental outcomes were measured at a mean age of 14.84 months and again at 4.8 years using specific assessment tools and tests.
Conclusion: Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. Associations seem dependent on frequency of exposure.
Authors: Claudia B. Avella-Garcia, Jordi Julvez, Joan Fortuny, Cristina Rebordosa, Raquel Garcia-Esteban; Isolina Riano Galan; Adonina Tardon; Clara L. Rodriguez-Bernal; Carmen Iniguez; Ainara Andiarena; Loreto Santa-Marina; and Jordi Sunyer.
Stergiakouli, E., et al. (2016). Association of Acetaminophen Use During Pregnancy with Behavioral Problems in Childhood: Evidence Against Confounding. JAMA Pediatrics.
This study collected data from the large, prospective birth cohort, Avon Longitudinal Study of Parents and Children, to look at associations between behavioral problems in children and maternal prenatal acetaminophen use, maternal postnatal acetaminophen use, and partner’s acetaminophen use. Mothers were asked about their acetaminophen use in the previous 3 months at 18 and 32 weeks of pregnancy and again when the child was 61 months old. The mother’s partner was also asked about acetaminophen use when the child was 61 months old. The children’s behavioral problems were assessed using a child behavior screening questionnaire.
Conclusion: Children exposed to acetaminophen prenatally are at increased risk of multiple behavioral difficulties and associations do not appear to be explained by unmeasured behavioral or social factors.
Authors: Evie Stergiakouli, Ph.D.; Anita Thapar FRCPsych, Ph.D.; and George Davey Smith, M.D. DSc.
Liew, Z., et al. (2016). Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. International Journal of Epidemiology.
This study used data from the Lifestyle During Pregnancy Study sub-cohort on 1491 mothers and children enrolled in Danish National Birth Cohort to evaluate the effects of prenatal acetaminophen use on attention and executive function in children. APAP use was obtained through three telephone interviews conducted at 12 and 30 weeks pregnant and 6 months after birth. Attention was measured by a series of comprehensive attention tests and executive function was measured using a questionnaire completed by the parent and preschool teacher.
Conclusion: There was some evidence that maternal paracetamol use during pregnancy was associated with poorer attention and executive function in five-year-olds.
Authors: Zeyan Liew; Cathrine Carlsen Bach; Robert F. Asarnow; Beate Ritz; and Jorn Olsen.
Bauer, A.Z., et al. (2018). Prenatal paracetamol exposure and child neurodevelopment: A review. Hormones and Behavior.
These authors conducted a review of publications reporting associations between prenatal APAP use and offspring neurodevelopmental outcomes. Of the 64 studies the authors retrieved, 55 were ineligible, so nine prospective cohort studies were reviewed. The authors utilized qualitative review methodology guidelines to evaluate key characteristics of each study. The aim of the study was to determine whether unmeasured behavioral factors linked to acetaminophen use may have confounded the association between prenatal acetaminophen use and abnormal fetal neurodevelopment.
Conclusion: All studies suggested association. A longer duration of use was associated with increased risk. Associations were strongest for hyperactivity and attention-related outcomes. Pregnant women should be cautioned against indiscriminate use of APAP.
Authors: Ann Z. Bauer; David Kriebel; Martha R. Herbert; Carl-Gustaf Bornehag; and Shanna H. Swan.
Golding, J., et al. (2019). Associations between paracetamol (acetaminophen) intake between 18 and 32 weeks gestation and neurocognitive outcomes in the child: A longitudinal cohort study. Pediatric and Perinatal Epidemiology.
This study was part of the Avon Longitudinal Study of Parents and Children and identified its aim as determining whether acetaminophen use at 18-32 weeks of pregnancy affected children’s neurocognition or behavior using a large population. The study looked at information on child cognitive and behavioral outcomes from 6 months to 17 years. The authors analyzed cognition using IQ test results, temperament using 11 temperament variables, and behavior using several measures.
Conclusion: Any adverse effect paracetamol use in mid-to-late pregnancy has on neurocognitive outcome appears mainly to relate to the pre-school period.
Authors: Jean Golding, Steven Gregory, Rosie Clark, Genette Ellis, Yasmin Iles-Caven, and Kate Northstone.
Ji, Y., et al. (2019). Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood. JAMA Psychiatry.
This was a prospective cohort study of 996 mother-infant dyads from Boston Birth Cohort aimed at examining the associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities in childhood.
Conclusion: Cord plasma biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood attention-deficit/hyperactivity disorder and autism spectrum disorder.
Authors: Ji Yuelong, Ph.D.; Romuladus E. Azuine, DrPH, MPH, RN; Yan Zhang, PhD; Wenpin Hou, PhD; Xiumei Hong, MD, PhD; Guoying Wang, MD PhD; Anne Riley, PhD; Colleen Pearson, BA; Barry Zuckerman, MD; and Xiaobin Wang, MD, MPH, ScD.
Bandoli, G., et al. (2020). Acetaminophen use in pregnancy: examining prevalence, timing and indication of use in a prospective birth cohort. Paediatr Perinat Epidemiol.
Data for this study was drawn from the prospective birth cohort study, MotherToBaby, of pregnant women between 2004-2018 to determine what indications and characteristics led to acetaminophen use during pregnancy.
Conclusion: The majority of women in the study used acetaminophen during pregnancy. Because the duration, indication, and dosage of such use is varied, studies should consider those factors in estimating the risk of adverse outcomes associated with acetaminophen use.
Authors: Gretchen Bandoli; Kristin Palmsten; and Christina Chambers.
Tronnes, J.N., et al. (2020). Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool-aged children. Paediatric and Perinatal Epidemiology.
Using data from Norwegian Mother and Child Cohort Study, this study employed linear models with inverse probability weights to quantify association between duration and timing of prenatal acetaminophen exposure and preschool aged-children’s communications skills, behavior, and temperament.
Conclusion: Timing of exposure and short-term use do not seem to pose substantial risk of the outcomes examined. There is association, but the authors could not rule out chance or unmeasured confounding as possible explanations.
Authors: Johanne N. Torres; Mollie Wood; Angela Lupattelli; Eivind Ystrom; and Hedvig Nordeng.
Wood, M. (2020). Associations between prenatal acetaminophen exposure and child neurodevelopment: Truth, bias, or a bit of both? Paediatric and Perinatal Epidemiology.
The author of this article discussed the recent studies suggesting prenatal exposure to acetaminophen is associated with neurodevelopmental problems in children.
Conclusion: Carrying out and interpreting studies of prenatal acetaminophen exposure are challenging. Research continues to show modest association between prenatal acetaminophen use and neurodevelopment in children and that more intense and prolonged exposure has larger effect, but very little residual confounding could explain observed effects.
Author: Mollie E. Wood.
Baker, B.H., et al. (2020). Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity. JAMA Pediatrics.
This was a birth cohort study of 345 children to determine whether prenatal acetaminophen exposure measured in meconium (the first stool of a newborn) was associated with ADHD and if the association was mediated by changes in brain connectivity.
Conclusion: Acetaminophen exposure detected in meconium was associated with increased odds of ADHD and altered brain connectivity between frontoparietal and default mode networks to sensorimotor cortices. Altered frontoparietal-sensorimotor cortex connectivity mediated an association of prenatal acetaminophen exposure with hyperactivity. ADHD and related brain phenotypes are associated with prenatal acetaminophen exposure measured directly in meconium.
Authors: Brennan H. Baker, MA; Claudia Lugo-Candeles, PhD; Haotian Wu, PhD; Hannah E. Laue, ScD; Amélie Boivin, MSc; Virginie Gillet, PhD; Natalie Aw, MS; Tonima Rahman, BS; Jean-Francois Lepage, PhD; Kevin Whittingstall, MD; Jean-Phillippe Bellenger, PhD; Jonathan Posner, MD; Larissa Takser, MD; and Andrea A. Baccarelli, MD, PhD.
Alemany, S., et al. (2021). Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. European Journal of Epidemiology.
This study aimed at examining the association between prenatal acetaminophen use and autism spectrum conditions and ADHD after reducing variability among cohorts used. Prenatal and postnatal acetaminophen exposure was assessed through maternal questionnaires or interviews. Symptoms of ASD and ADHD were assessed using questionnaires or hospital records.
Conclusion: Results indicated that children prenatally exposed were 19% and 21% more likely to have borderline or clinical ASD and ADHD symptoms, respectively.
Authors: Silvia Alemany, Claudia Avella-Garcia, Zeyan Liew, Raquel Garcia-Esteban, Kosuke Inoue, Tim Cadman, Monica Lopez-Vicente, Llucia Gonzalez, Isolina Riano Galan, Ainara Andiarena, Maribel Casas, Katerina Margetaki, Katrine Strandberg-Larsen, Deborah A. Lawlor, Hanan El Marroun, Henning Tiemeier, Carmen Iniguez, Adonina Tardon, Loreto Santa-Marina, Jordi Julvez, Daniela Porta, Leda Chatzi, and Jordi Sunyer.
Why is this important?
Research has shown that children with better attention and executive function do better in every aspect of life.
The employment rate is very low for individuals with ASD, as well as the rate of those who live without the need for help with daily activities. Only about 25% of individuals in the U.S. with ASD with average intelligence live on their own. Accordingly, the majority live with their families until they at least reach middle age. For those with ASD, marriage and long-term relationships are rare.
Compared with controls, once in their mid-twenties, those with ADHD complete less schooling, hold lower-ranking occupations, and suffer from poor self-esteem and social skills. A study by Kuriyan, et al. (2013) found that 15% of young adults diagnosed with ADHD hold a 4-year degree compared to 48% of the control group and .06% held a graduate degree compared to 5.4% of the control group. The same study also found that young adults with ADHD between the ages of 23 and 32 are more likely to be unemployed and not in school, more likely to be in unskilled versus clerical occupation, and more likely to be in unskilled versus professional occupations.
Krause & Kinsman first to file
Krause & Kinsman filed the first lawsuit in the country alleging manufacturers and sellers of acetaminophen knew or should have known of the significant risk that acetaminophen use during pregnancy causes autism disorder and/or ADHD but failed to warn of it. Our firm is actively pursuing this litigation, and we continue to accept cases involving prenatal use of acetaminophen and diagnoses of autism and/or ADHD to help families obtain justice.
Litigation Landscape
Between June and September 2022, dozens of lawsuits were filed against various manufacturers and retailers of acetaminophen around the country, including Arizona, Arkansas, California, Minnesota, Missouri, Nevada, and Washington, all raising similar allegations regarding the failure to warn about prenatal exposure to acetaminophen.
A hearing on a motion to consolidate these cases – to move them all to one court – was held on September 29, 2022, in St. Louis, Missouri. Krause & Kinsman supported consolidation of the cases, and Robert Kinsman presented oral argument at the hearing.
On October 11, 2022, the Panel considering the motion (the Judicial Panel on Multidistrict Litigation) determined that centralization of the actions would serve the convenience of the parties and witnesses and promote efficient conduct of the litigation and transferred the actions to Judge Denise L. Cote in the Southern District of New York for coordinated proceedings.
Judge Cote entered her first Case Management Order for the multi-district litigation (MDL) on October 18, 2022, setting the initial Pretrial Conference for November 17, 2022. The Order also establishes some rules for practice and procedure in the MDL and several deadlines for filings. This order was followed by an order entered on October 24, 2022, setting forth additional deadlines for filings leading up to the initial conference.
