Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort

Tovo‐Rodrigues, Luciana; Schneider, Bruna Celestino; Martins‐Silva, Thais; Del‐Ponte, Bianca; Mola, Christian Loret de; Schüler‐Faccini, Lavínia; Vianna, Fernanda Sales Luiz; Munhoz, Tiago N.; Entiauspe, Ludmila Gonçalves; Silveira, Mariângela Freitas da; Santos, Iná S.; Matijasevich, Alícia; Barros, Aluísio J. D.; Rohde, Luís Augusto; Bertoldi, Andréa Dâmaso

doi:10.1186/s12888-018-1942-1

Cited by 36 publications

(46 citation statements)

References 51 publications

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“…Tovo‐Rodrigues et al, reported sex‐specific findings in an analysis of the 2004 Pelotas Birth Cohort data. In that study, the authors found an adverse association of acetaminophen exposure with hyperactivity/inattention as well as emotional problems in boys at 6 years of age . Similar sex‐specific findings were observed by Avella‐Garcia et al, in which prenatal acetaminophen exposure was associated with a greater number of ASD symptoms in boys .…”

Section: Commentsupporting

confidence: 79%

Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood

Bertoldi

Rifas‐Shiman

Boing

et al. 2020

Paediatric Perinatal Epid

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Background: Over-the-counter analgesic use during pregnancy, particularly acetaminophen, may be associated with negative developmental outcomes in children.Objective: Estimate associations of prenatal and early-life exposure to acetaminophen in early childhood with cognitive, motor, and language skills in two birth cohorts. Methods: The American Project Viva cohort (1217 mother-child pairs enrolled 1999-2002) assessed cognition at approximately 3 years using the Peabody Picture Vocabulary Test and the Wide Range Achievement of Visual Motor Abilities (WRAVMA). The Brazilian 2015 Pelotas Birth Cohort (3818 mother-child pairs) assessed cognition at 2 years using the INTERGROWTH-21st NeurodevelopmentAssessment. We used linear regression to estimate associations of acetaminophen use during pregnancy (Project Viva and Pelotas) and infancy (Project Viva) with children's cognitive scores adjusted for maternal age, pre-pregnancy body mass index, education, parity, race/ethnicity, smoking and alcohol use during pregnancy, depression during pregnancy, antibiotic and ibuprofen use during pregnancy, household income, and child's sex. Results:In Project Viva, exposure to acetaminophen in both the 1st and 2nd trimester of pregnancy was associated with lower WRAVMA drawing scores (β −1.51, 95% CI −2.92, −0.10). However, in Pelotas, exposure to acetaminophen in both the 1st and 2nd trimester of pregnancy was not associated with INTER-NDA motor scores (β 0.02; 95% CI −0.05, 0.09) and was associated with higher INTER-NDA total scores (β 0.08, 95% CI 0.01, 0.16). Other comparisons did not show evidence for any associations. Conclusions:Inconsistencies and lack of specificity of the findings did not clarify the research question considering that we still have a large variability and uncertainty to define the risk or safety in the use of acetaminophen related to cognition in early childhood. More studies using better exposure assessment and better confounding variables are needed to clarify these associations.

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Section: Commentsupporting

confidence: 79%

Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood

Bertoldi

Rifas‐Shiman

Boing

et al. 2020

Paediatric Perinatal Epid

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“…In the Brazilian 2004 Pelotas birth cohort, 6‐year‐old boys of mothers who used acetaminophen in pregnancy had higher odds of emotional (OR 1.47, 95% CI 1.07, 2.02) and hyperactivity (OR 1.42, CI 1.06, 1.92) problems, as assessed by parent‐reported SDQ scores . At age 11 years, there was a small decrease in these associations (emotional OR 1.31, CI 0.99, 1.73 and hyperactivity OR 1.25, CI 0.95, 1.65 problems).…”

Section: Discussionmentioning

confidence: 99%

“…Prior investigators have suggested that child sex may modify associations between acetaminophen exposure and behavioural outcomes . We assessed potential effect measure modification by re‐running adjusted models stratified by sex and also computed interaction P ‐values.…”

Section: Methodsmentioning

confidence: 99%

“…The US Food and Drug Administration considers acetaminophen the safest analgesic to take throughout pregnancy and recommends avoiding ibuprofen in the third trimester due to an increased risk of birth defects . However, acetaminophen readily crosses the placenta, and multiple human and animal studies suggest that prenatal acetaminophen use is associated with abnormal offspring neurodevelopment . The mechanism may involve disrupted endocrine function, which has been shown in animal studies to affect fetal brain development .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, few prior studies examined prenatal exposure to ibuprofen, or acetaminophen and ibuprofen use by the child in infancy . Also, behavioural outcomes in most prior studies were reported by mothers only (vs both mothers and teachers) . Subtle, subclinical behaviour problems may be more apparent in a school setting rather than at home; and any bias in reporting of outcomes by teachers is less likely related to prenatal and infant analgesic use, minimising misclassification.…”

Section: Introductionmentioning

confidence: 99%

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

Rifas‐Shiman

Cárdenas

Hivert

et al. 2019

Paediatric Perinatal Epid

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Background: Over-the-counter analgesics during pregnancy or infancy may be related to neurobehavioural problems in children, but little is known about effects of different analgesic types, dosage, and timing.Objectives: Examine associations of acetaminophen and ibuprofen use during pregnancy and infancy with executive function and behaviour problems in children. Methods:We included 1225 mother-child pairs from Project Viva, a pre-birth cohort study. We assessed prenatal acetaminophen and ibuprofen use in early and mid-pregnancy and infant use in the first year of life using questionnaires. Parents and classroom teachers assessed child behaviours in mid-childhood (median 8 years), using the Behavior Rating Inventory of Executive Function (BRIEF) and the Strengths and Difficulties Questionnaire (SDQ), with higher scores indicating worse functioning for both. We examined associations of acetaminophen and ibuprofen use during pregnancy and infancy with mid-childhood neurobehavioural outcomes using linear regression models adjusted for potential confounders.Results: During pregnancy, 46.1% of mothers used acetaminophen ≥10 times and 18.4% used any ibuprofen. In the first year, 65.3% and 39.6% of infants received acetaminophen and ibuprofen ≥6 times, respectively. Higher (≥10 vs <10 times) prenatal acetaminophen (β 1.64 points; 95% confidence interval [CI] 0.59, 2.68) and any ibuprofen (β 1.56, 95% CI 0.19, 2.92) were associated with higher parent-rated BRIEF global scores. Patterns of association were linear across categories and were similar for other parent-and teacherrated outcomes. Infancy exposure (≥6 vs <6 times) to acetaminophen (β 1.69, 95% CI 0.51, 2.87) and ibuprofen (β 1.40, 95% CI 0.25, 2.55) were associated with higher parent-rated BRIEF GEC scores but associations with teacher-rated scores were weaker.Conclusions: Prenatal and early-life exposure to acetaminophen and ibuprofen were associated with poorer executive function and behaviour in childhood. These findings highlight the need for further research on the mechanisms through which analgesics may act on fetal and child brain development. K E Y W O R D Sacetaminophen, child behaviour, child executive function, ibuprofen, infancy, pregnancy

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Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood

et al. 2020

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Prior studies have raised concern about maternal acetaminophen use during pregnancy and increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in their children; however, most studies have relied on maternal self-report.OBJECTIVE To examine the prospective associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities (DDs) in childhood. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study analyzed 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018.EXPOSURES Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-L-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth. MAIN OUTCOMES AND MEASURESPhysician-diagnosed ADHD, ASD, and other DDs as documented in the child's medical records. RESULTSOf 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical. Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60). Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD. CONCLUSIONS AND RELEVANCECord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion. Our findings support previous studies regarding the association between prenatal and perinatal acetaminophen exposure and childhood neurodevelopmental risk and warrant additional investigations.

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Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort

Cited by 36 publications

References 51 publications

Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood

Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood

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

Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood

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