Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies

Abstract

Acetaminophen is the most commonly used analgesic and antipyretic during pregnancy. Evidence of neuro-disruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, EMBASE, and Cochrane up to January 2017. Data were independently extracted and assessed by two researchers. Seven eligible retrospective cohorts included 132,738 mother and child pairs and with a follow-up period of 3-11 years. Pooled risk ratio (RR) for ADHD was (RR=1.32, 95% CI 1.18,1.45, I2=61%), for ASD (RR=1.23, 95% CI1.13,1.32, I2=17%), and for hyperactivity symptoms (RR=1.23, 95% CI 1.01,1.49, I2=94%). In meta-regression analysis, the association between exposure and ADHD increased with childs' age upon follow-up and with the mean duration of exposure (β=0.0354, 95% CI 0.001,0.07), (β=0.006, 95% CI 0.009,0.01). The available data is of observational nature only. Studies differed gravely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD and hyperactivity symptoms. These findings are concerning, however, results should be interpreted with caution as the available evidence consists of observational studies and susceptible to several potential sources of bias.

Associations of prenatal or infant exposure to acetaminophen or ibuprofen with mid‐childhood executive function and behaviour

“…Our results are consistent with previous studies that reported associations of acetaminophen in pregnancy with greater childhood executive function and behaviour problems . Studies in Spain, New Zealand, United Kingdom, Denmark, and Norway have reported associations of prenatal acetaminophen use with offspring behavioural problems, symptoms of attention deficit/hyperactivity disorder, and diagnosis with an autism spectrum disorder at school age.…”

“…In a 2018 meta‐analysis of 7 studies including 132 738 participants, prenatal exposure to acetaminophen was associated with a 20%‐30% increase in the risk of neurodevelopmental disorders, including attention deficit hyperactivity disorder, autism spectrum disorders, and hyperactivity symptoms . However, there was evidence of heterogeneity between study estimates of the outcomes.…”

“…However, there was evidence of heterogeneity between study estimates of the outcomes. An important additional limitation of the included studies was the potential for confounding by indication . In addition, few prior studies examined prenatal exposure to ibuprofen, or acetaminophen and ibuprofen use by the child in infancy .…”

Autism‐related behaviors in the cyclooxygenase‐2‐deficient mouse model

“…Furthermore, misuse of the drug misoprostol—a PGE2 analogue—for the termination of pregnancy was linked to elevated risk of ASD . We also previously reported that PGE2 signaling in the developing brain is especially vulnerable to various environmental insults such as inflammation, oxidative stress, pollution, heavy metals, pesticides and commonly used over‐the‐counter drugs like acetaminophen and nonsteroidal anti‐inflammatory drugs including acetylsalicylic acid, which all have been linked to ASD …”

“…44 We also previously reported that PGE2 signaling in the developing brain is especially vulnerable to various environmental insults such as inflammation, oxidative stress, pollution, heavy metals, pesticides and commonly used over-the-counter drugs like acetaminophen and nonsteroidal anti-inflammatory drugs including acetylsalicylic acid, which all have been linked to ASD. [19][20][21]45 Emerging molecular evidence offers insight into possible mechanisms by which abnormal COX2/PGE2 signaling may affect brain development and lead to autism. For example, in vitro studies in our laboratory have shown that elevated levels of PGE2 can modify intracellular calcium dynamics and increase neural proliferation, migration and differentiation in neural stem cells and differentiating neurons.…”