Association of Prenatal Acetaminophen Exposure With Risk of ADHD and ASD in Offspring: A systematic review and meta-analysis

Introduction The association between prenatal acetaminophen exposure and the development of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) remains a subject of considerable debate. Despite extensive research, the evidence regarding this relationship is conflicting. Objectives To perform a systematic review and meta-analysis of studies comparing the incidence of ADHD and ASD in patients that were either exposed or not exposed to acetaminophen prenatally. Methods We systematically searched Pubmed, Embase and Cochrane Central for eligible studies up until August 2024. Only studies which included participants with a medical diagnosis of ADHD/ASD and reported acetaminophen exposure as a binary measure were included. Available summary data was extracted from published reports and pooled with a random-effects model using odds ratios (OR) with 95% confidence intervals (CI). Hazard ratios (HR) adjusted for potential confounding factors were used for sensitivity analyses. All statistical analyses were conducted utilizing Review Manager 5.4.1. PROSPERO iD:CRD42024587662. Results We included five studies with a total of 2,647,536 patients with ADHD (150,741) / ASD (63,726), of whom 271,126 were exposed to acetaminophen prenatally and 2,376,410 were not exposed. Prenatal acetaminophen exposure was associated with an increased risk of developing ADHD (OR 1.30; 95% CI 1.17 to 1.45; p<0.01; I2 = 73%; Figure 1) and ASD (OR 1.17; 95% CI 1.14 - 1.20; p<0.01; I2 = 0%; Figure 2). Sensitivity analyses revealed that acetaminophen exposure during the third trimester of pregnancy was associated with an increased risk of ADHD (HR 1.26; 95% CI 1.07 to 1.47; p<0.01; I2 = 0%; Figure 3), but not during first (HR 1.10; 95% CI 0.97 to 1.26; p=0.13; I2 = 0%; Figure 3) and second (HR 1.07; 95% CI 0.95 to 1.19; p=0.26; I2 = 0%; Figure 3) trimesters. Image 1: Image 2: Image 3: Conclusions In this systematic review and meta-analysis, prenatal acetaminophen exposure was significantly associated with risk of developing ADHD and ASD, especially if exposure occurs in the third trimester of pregnancy. Disclosure of Interest None Declared