Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool‐aged children

Abstract

Background: Recent studies have suggested an association between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in children. However, these findings may be confounded by unmeasured factors related to maternal use of paracetamol and child outcomes.Objective: To examine the association between duration and timing of prenatal paracetamol exposure on parent-reported communication skills, behaviour, and temperament in preschool-aged children, with focus on the role of unmeasured confounding. Methods:We used data from the Norwegian Mother and Child Cohort Study. Linear and generalised linear models with inverse probability weights and robust standard errors were used to quantify the association between prenatal paracetamol exposure and continuous and categorical outcomes. Results:Of the 32 934 children included in our study, 8374 (25.4%), 4961 (15.1%), and 1791 (5.4%) were prenatally exposed to paracetamol in one, two, and three trimesters, respectively.Children exposed to paracetamol in two trimesters scored lower on shyness compared with unexposed children (β −0.62, 95% confidence interval [CI] −1.05, −0.19). Children exposed to paracetamol in three trimesters had a moderate increased risk of internalising behaviour problems (relative risk (RR) 1.36, 95% CI 1.02, 1.80) and borderline externalising behaviour problems (RR 1.22, 95% CI 0.93, 1.60) compared with unexposed children. Children exposed to paracetamol in 2nd/3rd trimester scored lower on shyness (β −0.32, 95% CI −0.66, 0.02) compared with unexposed children. Sensitivity analyses indicated that unmeasured confounders play an important role and may potentially bias the effect estimates away from the null. Conclusions:Timing of exposure and short-term use of paracetamol during pregnancy do not seem to pose any substantial risk of the outcomes examined. Although we found an association between paracetamol use in multiple trimesters and lower shyness and greater internalising behaviour in preschool-aged children, we cannot rule out chance or unmeasured confounding as possible explanations for these findings. K E Y W O R D Schild neurodevelopment, MoBa, paracetamol, pregnancy This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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.…”

“…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. On balance, the information bias in these studies should move estimates towards the null: this is a reasonable expectation with dichotomous exposures.…”

“…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.…”

“…This suggests that the underlying indications and causes of exposure are complex and points to a potential for heritable or familial confounding by susceptibility to psychiatric co‐morbidities. All of the included studies used an analytic method for control of measured confounders, including multivariable adjustment or inverse probability (of treatment) weighting . In addition, some used a negative control or other sensitivity analyses to understand the possible impact of unmeasured confounding.…”