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

Abstract

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

Associations between prenatal acetaminophen exposure and child neurodevelopment: Truth, bias, or a bit of both?

“…Given that all exposure collected in the included studies involved some degree of recall, with latency ranging from weeks to years, some degree of misclassification is inevitable. Further, several studies included self‐reported exposure and outcome data from the same source (ie maternal report), which may leave them vulnerable to dependent measurement error. If over‐reporting of exposures co‐occurs with over‐reporting of outcomes, for example, this could produce the appearance of a strong effect of exposure on outcome.…”

“…If over‐reporting of exposures co‐occurs with over‐reporting of outcomes, for example, this could produce the appearance of a strong effect of exposure on outcome. Several studies addressed this by using multi‐informant ascertainment, such as including reports from both the parent and a teacher, or including a clinical evaluation of neurodevelopment . In two studies, parent and teacher reports diverged, but in a third they did not, making this difficult to interpret.…”

“…Several studies addressed this by using multi‐informant ascertainment, such as including reports from both the parent and a teacher, or including a clinical evaluation of neurodevelopment . In two studies, parent and teacher reports diverged, but in a third they did not, making this difficult to interpret. One study used probabilistic bias analysis to quantify the potential impact of exposure misclassification, noting that realistic levels of misclassification could have substantially attenuated the observed effect estimates.…”

“…Selection is also a plausible source of bias. Most of the studies included in this special issue of Paediatric and Perinatal Epidemiology had lost more than half of their original sample to follow‐up between birth and the time of neurodevelopmental assessment, shown in panel B of the figure as loss to follow‐up. If children not available for assessment have different neurodevelopmental profiles then those present at follow‐up, this could be a source of bias if loss to follow‐up is also associated with exposure, either directly or through a backdoor path.…”

“…Conversely, mothers using less acetaminophen might participate less often, which could produce bias away from the null. Several of the studies in this issue used weighting methods to account for measured predictors of loss to follow‐up, but noted minimal differences between weighted and unweighted estimates, suggesting that selection bias may not be a major threat to validity in this instance. Alternately, there may be common causes of exposure and selection that were not included in the weights.…”