The U.S. Food and Drug Administration (FDA) recently published a press announcement that they will be initiating a label change for acetaminophen and other products due to growing evidence of acetaminophen use in pregnant women potentially linking to increased risk of neurological conditions such as autism in children. However, while an association is described in many studies, a causal relationship has not been established, and there are contrary studies in the scientific literature. [1]
A 2021 meta-analysis examined the association between prenatal and postnatal acetaminophen exposure and the development of autism spectrum conditions (ASC) and attention-deficit/hyperactivity disorder (ADHD) symptoms in childhood. This comprehensive analysis leveraged data from six European population-based birth cohorts involving a total of 73,881 mother-child pairs. The study utilized maternal questionnaires and interviews to gather information on acetaminophen use during pregnancy and up to 18 months postnatally. Validated instruments assessed ASC and ADHD symptoms in children aged 4 to 12 years, classifying their symptoms as borderline or clinical using recommended cutoffs for each instrument. Cohort-specific effect estimates were adjusted for a range of maternal and child characteristics and combined through random-effects meta-analysis. Results indicated that prenatal acetaminophen exposure was associated with a 19% increase in the odds of developing borderline or clinical ASC symptoms (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.07 to 1.33) and a 21% increase in ADHD symptoms (OR 1.21; 95% CI 1.07 to 1.36) compared to non-exposed children. Notably, the associations were more pronounced in boys compared to girls. In contrast, postnatal acetaminophen exposure did not demonstrate a statistically significant association with either ASC or ADHD symptoms. Although the results suggest a risk when exposing pregnant women to acetaminophen, limitations due to variability in assessing ASC and ADHD and confounding variables greatly limit the strength of findings. [2]
A 2018 systematic review, meta-analysis, and meta-regression analysis evaluated the impact of prenatal exposure to acetaminophen on the risk of developing ADHD and ASD in offspring. The research synthesized data from seven eligible retrospective cohort studies encompassing a total of 132,738 mother-child pairs, with follow-up periods ranging from 3 to 11 years. The pooled risk ratio (RR) indicated a significant association between prenatal acetaminophen exposure and the risk of ADHD (RR 1.32; 95% CI 1.18 to 1.45; I2= 61%), ASD (RR 1.23; 95% CI 1.13 to 1.32; I2= 17%), and hyperactivity symptoms (RR 1.24; 95% CI 1.02 to 1.46; I2= 95%). Through meta-regression analysis, several study-level covariates were explored for their potential modifying effects on the observed associations. Notably, the strength of the association between acetaminophen exposure and ADHD diagnosis was found to increase with the age of the child at follow-up (β= 0.0354; 95% CI 0.001 to 0.07) and the duration of maternal acetaminophen use during pregnancy (β=0.006; 95% CI 0.009 to 0.01). Conversely, younger maternal age appeared to mitigate this association (β= -0.17; 95% CI -0.28 to -0.6). The comprehensive analysis highlights concerns regarding the neuro-disruptive potential of acetaminophen but advises cautious interpretation due to the observational nature of the included studies and the inherent susceptibility to biases such as confounding by indication and recall bias. [3]
A 2022 systematic review evaluated the evidence surrounding the safety of paracetamol (acetaminophen) use in infants and children with regard to neurodevelopment. A comprehensive literature search of PubMed for publications between 1974 and 2017 identified 218 papers making claims about the safety of paracetamol for use in infants or children. Upon deeper examination, 103 papers were cited as providing the authority for these safety claims, including 52 that described experiments testing safety, though none monitored neurodevelopmental outcomes, and had a median follow-up time of only 48 hours. This systematic evaluation noted that evidence supporting its safety largely stemmed from historical practices and the absence of observed acute liver damage in infants or children, rather than reassurance on long-term neurodevelopmental outcomes. [4]
A 2025 comprehensive systematic review applied the Navigation Guide methodology to scrutinize the potential association between prenatal acetaminophen exposure and the development of neurodevelopmental disorders (NDDs) in offspring, including ASD. The study meticulously followed a systematic approach, employing a thorough literature search in PubMed, ISI Web of Science, and Google Scholar to identify relevant observational studies and meta-analyses on the subject. Inclusion criteria encompassed original research that explored prenatal acetaminophen exposure, specifically focusing on neurodevelopmental outcomes such as ASD and ADHD. The research employed a Population, Exposure, Comparator, Outcome (PECO) framework to ensure systematic selection and assessment of the studies. The detailed analysis incorporated 46 studies, revealing a preponderance of evidence indicating a positive association between prenatal acetaminophen use and heightened risks of ADHD and ASD, among other NDDs. Specifically, 27 studies demonstrated significant links to NDDs, while nine reported null associations, and four suggested negative associations or protective effects. Higher-quality studies, typically those with more rigorous control for confounding factors and bias, consistently reported stronger associations. Specifically, the study included 20 studies on ADHD, 8 on ASD, and 18 on other NDDs, with risk-of-bias ratings conducted across domains such as confounding, exposure assessment, and outcome measurement. [5]
A 2022 systematic review examined the potential link between acetaminophen use during pregnancy and its effects on neurodevelopmental outcomes in offspring, with a particular focus on ASD. An extensive literature search of only recent, high-quality studies yielded 16 studies, consisting of 13 prospective cohort studies, 2 reviews, and 1 meta-analysis, all of which similarly demonstrated an association between acetaminophen exposure and adverse neurodevelopmental outcomes, including ASD, ADHD, and impaired IQ. Within the studies reviewed, varied neurodevelopmental parameters were assessed, such as ADHD, communication, behavior, and psychomotor development. However, findings across these studies highlighted that long-term and heightened frequency of acetaminophen use during pregnancy were more linked to an increased risk of ASD and ADHD than other neurodevelopmental impairments, with a notable dose-response relationship. The review underscores an urgent need for further research to delineate the underlying mechanisms of this association, including the role of genetics, the immune system, and precise mechanism of action leading to increased risk, given the widespread use of acetaminophen as an analgesic during pregnancy. Additionally, the review suggests cautious use of acetaminophen among expectant mothers until more definitive evidence regarding its safety is established. [6]
A 2024 clinical perspective examined the impact of maternal acetaminophen use during pregnancy on the risk of ADHD and ASD in children. The analysis critically reviewed nine studies with original data and three meta-analyses from a total of 56 identified publications. These studies were chosen based on stringent criteria regarding the quality and validity of ADHD or ASD outcome definitions. The review found that most studies reporting positive correlations were marred by significant biases, including a high degree of selection bias, variability in the selection and adjustment for potential confounders, and insufficient control for familial heritability. Notably, studies that included sibling analyses showed that associations significantly weakened once familial confounding was controlled for, indicating that shared genetic and environmental factors might have introduced an upward bias in earlier findings. The recent publication emphasized that, based on current scientific evidence, in utero exposure to acetaminophen is unlikely to significantly increase the risk of childhood ADHD or ASD. The methodological challenges identified in existing studies, such as insufficient control for shared familial factors and reliance on less rigorous diagnostic criteria, suggest caution in interpreting prior positive associations. The publication suggested that current existing data on treating pain and fever in pregnancy with acetaminophen does not support a clinically important increased risk of childhood ASD or ADHD from in utero exposure, and clinical guidance should remain unchanged. [7]