Preliminary models are shown in eTable 5 in Supplement 1. In final adjusted models in the population-based sample, children exposed to acetaminophen were slightly more likely to be diagnosed with autism (HR, 1.05 [95% CI, 1.02-1.08]; e-value, 1.28), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; e-value, 1.34), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; e-value, 1.28) compared with children not exposed to acetaminophen (Figure 3; eTable 6 in Supplement 1). Differences in absolute risk between acetaminophen users and nonusers were small. For example, for the population-based adjusted model of acetaminophen and autism, the absolute risk at 10 years was 0.09% higher with acetaminophen use (Figure 3; eTable 7 in Supplement 1). E-values indicated that an unobserved confounder would have to be only modestly associated with both the exposure and outcome to nullify the above associations. Sensitivity analysis using Cox models without sibling control in the full sibling cohort demonstrated that the sibling sample had the same apparent acetaminophen outcome associations as the total sample (eAppendix 2 and eTable 8 in Supplement 1).

Quiz Ref ID In contrast, in models with sibling control, acetaminophen was not associated with children’s risk autism (HR, 0.98 [95% CI, 0.93-1.04]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]) (Figure 3; eTable 6 in Supplement 1).

Figure 3:
Caption: Association Between Analgesic Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability
Description: Absolute risk difference is the difference in absolute risk at 10 years of age between exposed and unexposed children, expressed as a percentage. For example, the 0.09% absolute difference for acetaminophen and autism can be interpreted as follows: the risk of child autism at 10 years of age is 0.09% higher with acetaminophen use compared with no acetaminophen use. The population-based model was adjusted for birth cohort; child sex; all other analgesics; birthing parent’s diagnoses of migraine, chronic pain, infections, fevers, rheumatoid arthritis, and headaches; calendar period of delivery; parity; age at delivery (linear and cubic term); country of birth; residential region; cohabitation at delivery; early pregnancy body mass index; smoking status; diagnosis of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability; history of psychiatric conditions and prescription use of psycholeptics, antidepressants, and antiseizure medication; health care visits in the year before pregnancy and an inadequate number of antenatal visits; and the highest household education and disposable income. The sibling control model was adjusted for all of the above excluding birthing parent’s birth country, psychiatric history, and diagnosis autism, ADHD, and intellectual disability. NSAID indicates nonsteroidal anti-inflammatory drug.

Acetaminophen is the analgesic and antipyretic most commonly used during pregnancy. Evidence of neurodisruptive 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 databases for relevant studies up to January 2017. Data were independently extracted and assessed by 2 researchers. Seven eligible retrospective cohorts included 132,738 mother-child pairs, with follow-up periods ranging from 3 to 11 years. The pooled risk ratio for ADHD was 1.34 (95% confidence interval (CI): 1.21, 1.47; I2 = 72%); for ASD, the risk ratio was 1.19 (95%

Ci: 1.14, 1.25; I2 = 14%), and for hyperactivity symptoms, it was 1.24 (95%

Ci: 1.04, 1.43; I2 = 93%). In meta-regression analysis, the association between exposure and ADHD increased with the child's age upon follow-up (β = 0.03, 95%

Ci: 0.00, 0.07) and with the mean duration of exposure (β = 0.00, 95%

Ci: 0.00, 0.01). The available data is of observational nature only. Studies differed widely 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 given that the available evidence consists of observational studies and is susceptible to several potential sources of bias.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

Background: Maternal acetaminophen use during pregnancy is common globally. However, its potential risks for neurodevelopmental disorders in offspring, including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), remain uncertain in Asian populations.

Objective: We examined the association between maternal acetaminophen use during pregnancy and diagnoses of neurodevelopmental disorders in offspring.

Methods: This nationwide birth cohort study included 217,602 children contributing 966,546 person-years using a nationwide administrative database from 2005 to 2022. We investigated the association between maternal acetaminophen use during pregnancy and offspring's neurodevelopmental outcomes using Cox proportional hazards models, with primary analyses based on 1:1 propensity score (PS) matching. The robustness of the primary findings was evaluated through alternative statistical approaches (adjusted model and inverse probability of treatment weighting [IPTW]), sibling comparison, probabilistic bias analyses for exposure misclassification, and negative exposure control methods.

Results: Of the 217,602 children, 85,853 (39.5%) were exposed to acetaminophen during pregnancy. PS-matched analyses (N = 42,123 children per comparator) yielded hazard ratios of 1.08 (95%

Ci: 1.00, 1.16) for composite neurodevelopmental outcomes, 1.22 (95%

Ci: 1.09, 1.36) for ADHD, 1.06 (95%

Ci: 0.98, 1.15) for ASD, and 1.02 (95%

Ci: 0.90, 1.19) for ID. Similar findings were observed in adjusted models and IPTW methods. Sibling comparisons (n = 23,593) showed point estimates in the opposite direction (e.g., HR of ADHD, 0.86; 95% CI, 0.52, 1.44). Probabilistic bias analysis for exposure misclassification suggested overestimation due to unrecorded over-the-counter acetaminophen use, with effect estimates shifting towards the null as misclassification increased. Negative exposure controls (e.g., NSAIDs and acetaminophen use after pregnancy) indicated potential positive bias in the observed associations.

Conclusions: Although PS-matched analyses indicated small increases in risk, sensitivity analyses suggested that unmeasured confounding, misclassification and other biases may partially explain these associations.

Acetaminophen is a common over-the-counter medication that recently gained substantial media attention regarding its use by pregnant individuals. In this clinical perspective, we discuss the strengths and limitations of the published literature on the effect of maternal acetaminophen use in pregnancy on the child's risk of developing attention-deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies included were specifically selected on the basis of the quality and validity of ADHD or ASD outcome definitions. From a total of 56 identified studies, commentaries, and editorials of relevance, we critically reviewed nine studies with original data that satisfied our inclusion criteria and three meta-analyses. Most studies that have reported positive findings are difficult to interpret because they have important biases, notably a high degree of selection bias, variability in selection and adjustment for various potential confounders, and unmeasured familial confounding. When unobserved familial confounding through sibling analysis was controlled for, associations weakened substantially. This suggests that residual confounding from shared genetic and environmental factors may have caused an upward bias in the original observations. According to the current scientific evidence, in utero exposure to acetaminophen is unlikely to confer a clinically important increased risk of childhood ADHD or ASD. The current level of evidence does not warrant changes to clinical guidelines on the treatment of fever or pain in pregnancy. Prospective research designed to account for familial and psychosocial environmental factors related to both maternal use of acetaminophen and children's neurodevelopment should be undertaken.

Dyads included in these analyses were more likely to have a Hispanic mother (23.8% vs 21.6%; P = .02), be older (9.52 vs 8.62 years; P < .001), and be male (55.0% vs 48.3; P < .001); and less likely to have had a preterm birth (17.9% vs 33.7%; P < .001) and low birth weight (17.2 vs 32.3; P < .001) (eTable 1 in the Supplement).

All cord acetaminophen metabolites showed similar significant positive associations with the risk of ADHD diagnosis. The point estimates of the odds ratios (ORs) vary from 1.69 to 2.88 for ADHD and 1.38 to 3.72 for ASD (Table 2). Moreover, we identified dose-response patterns for cord unchanged acetaminophen and cord acetaminophen burden with the risk of ADHD. For instance, compared with being in the first tertile, being in the second tertile of cord acetaminophen burden was associated with 126% higher odds of ADHD diagnosis (OR, 2.26; 95% CI, 1.40-3.69), and being in the third tertile was associated with 186% higher odds of ADHD diagnosis (OR, 2.86; 95% CI, 1.77-4.67). Cord unchanged acetaminophen, cord acetaminophen glucuronide, and cord acetaminophen burden were also significantly associated with increased risk of ASD diagnosis. For instance, the third tertile cord acetaminophen burden was associated with 262% higher odds of ASD diagnosis compared with the first tertile (OR, 3.62; 95% CI, 1.62-8.60).

Table 2:
Caption: Adjusted Associations Between Cord Plasma Acetaminophen Biomarkers and the Risk of Physician-Diagnosed Conditionsa

Acetaminophen is the most commonly used medication for analgesic and antipyretic purposes among mothers during pregnancy and infants in early life. More than 65% of women in the United States and 50% in Europe ever used acetaminophen during pregnancy. Despite its widespread use, previous studies in animals and humans have found an association between prenatal acetaminophen exposure and increased risks of adverse childhood outcomes, including asthma, cryptorchidism, and neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Studies in rodents reported acetaminophen toxicity in cortical neurons and inhibition of fetal testosterone production, which would critically disrupt brain development. In addition, the therapeutic effect of acetaminophen can selectively inhibit cyclooxygenase 2, which may affect multiple brain functions, including long-term potentiation, spatial learning, and cerebellar development.

Human studies have found that acetaminophen could cross the human placental barrier and remain in an infant’s blood circulation for a long duration. Ecologic and cohort studies have found an association between maternal acetaminophen use and risk of ADHD and ASD. In the past 5 years, an increasing number of large, prospective cohort studies (mostly from Europe) found significant associations between maternal self-reported acetaminophen use during pregnancy and increased risk of ADHD and related symptoms in offspring in later life. In addition, a longer duration of reported use was also associated with higher risk of ADHD. Two recent meta-analyses found significant associations between maternal-reported acetaminophen use during pregnancy and the risk of ADHD.

However, the Society for Maternal-Fetal Medicine (SMFM) and the US Food and Drug Administration (FDA) have refrained from making recommendations regarding use, citing limited evidence and methodologic concerns, including recall bias, lack of dose information, potential residual confounders, and multiple testing. Nonetheless, the FDA has called on pregnant women and health care professionals to carefully evaluate the benefits and risks of using acetaminophen during pregnancy. Similarly, the American Academy of Pediatrics (AAP) Grand Rounds concluded that there was no definitive causal link between acetaminophen exposure and ADHD.

Background: Acetaminophen is the most commonly used over-the-counter pain and fever medication taken during pregnancy, with > 50% of pregnant women using acetaminophen worldwide. Numerous well-designed studies have indicated that pregnant mothers exposed to acetaminophen have children diagnosed with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), at higher rates than children of pregnant mothers who were not exposed to acetaminophen.

Methods: We applied the Navigation Guide methodology to the scientific literature to comprehensively and objectively examine the association between prenatal acetaminophen exposure and NDDs and related symptomology in offspring. We conducted a systematic PubMed search through February 25, 2025, using predefined inclusion criteria and rated studies based on risk of bias and strength of evidence. Due to substantial heterogeneity, we opted for a qualitative synthesis, consistent with the Navigation Guide's focus on environmental health evidence.

Results: We identified 46 studies for inclusion in our analysis. Of these, 27 studies reported positive associations (significant links to NDDs), 9 showed null associations (no significant link), and 4 indicated negative associations (protective effects). Higher-quality studies were more likely to show positive associations. Overall, the majority of the studies reported positive associations of prenatal acetaminophen use with ADHD, ASD, or NDDs in offspring, with risk-of-bias and strength-of-evidence ratings informing the overall synthesis.

Conclusions: Our analyses using the Navigation Guide thus support evidence consistent with an association between acetaminophen exposure during pregnancy and increased incidence of NDDs. Appropriate and immediate steps should be taken to advise pregnant women to limit acetaminophen consumption to protect their offspring's neurodevelopment.