Low neurodevelopmental performance and behavioural/emotional problems at 24 and 48 months in Brazilian children exposed to acetaminophen during foetal development

What are we to make of a recent flood of studies suggesting that prenatal exposure to acetaminophen is associated with neurodevelopmental problems in toddlers and young children? Neurodevelopment is a notoriously slippery outcome to define, as it encompasses multiple phenotypes, including cognition and intelligence, psychiatric diagnoses, developmental milestone attainment, behavioural problems, motor and communication skills, and emotional regulation.Others have noted that many of the survey-based instruments used to measure neurodevelopment have uncertain predictive value for clinically relevant developmental problems. 1 Even assuming that studies have selected outcome measures that capture important neurodevelopmental phenotypes, studying the effect of acetaminophen on these outcomes is extraordinarily challenging. Nonetheless, acetaminophen is one of the most commonly used medications among pregnant women, and if prenatal exposure truly has a causal effect on neurodevelopment, even if this effect is small, it is important to understand it.Consider the hypothetical case where acetaminophen has a true causal effect on neurodevelopment, but affects only impulsivity, and only for exposures occurring between gestational weeks 17 and 20.Acetaminophen is highly subject to exposure misclassification, both in terms of confusion with other drugs and with respect to timing of use. Many studies rely on maternal report for both the exposure and the outcome, which can introduce dependent measurement error. Acetaminophen is taken for a wide range of reasons and severity, including pain, inflammation, and fever, making confounding by indication very difficult to understand and control, either through design or analysis. Ascertainment of neurodevelopmental problems often requires follow-up over the course of years, leaving the sample vulnerable to bias from selection, especially if parents of children with more behavioural problems are less likely to sustain their participation in a long-term study, and if participation is also associated with exposure. Considered singly, any one of these sources of bias should worry conscientious researchers, but taken together, a picture of multiple competing biases emerges, making the task of identifying a true causal effect very challenging. The figure depicts the classic threats to validity-information, selection, and confounding bias-in terms of how they are likely to move effect estimates in studies of prenatal exposure to acetaminophen and neurodevelopmental outcomes in children (panel A), and a possible directed acyclic graph (panel B) suggests a possible causal mechanism through which these biases may act.

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confidence: 98%

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confidence: 99%

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confidence: 99%

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

Wood

2020

“…These studies represent a comprehensive epidemiologic investigation of the topic, as they featured a range of designs (cohort; meta‐analysis), informants (parent, teacher, and researcher), ages at assessment (2‐16 years), domains of functioning (psychopathology symptoms and receptive vocabulary), objectives (confounder identification and effect estimation), and settings (United States; United Kingdom; Brazil; Norway). Despite such marked variability in approach, five of the six studies that included childhood assessment data reported links between self‐reported acetaminophen use and at least one aspect of behavioural‐level functioning . However, several issues undermine this appearance of replicability, instead raising questions regarding clinical relevance and the plausibility of causal links.…”

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confidence: 99%

Prenatal acetaminophen exposure and neurodevelopment: State of the evidence

Talge

2020

The developing brain is a fascinating enigma-it is vulnerable to the impacts of deleterious exposures, yet it simultaneously exhibits a remarkable capacity for resilience and adaptation. This apparent paradox can be explained by the concept of sensitive periods, timeframes in which the presence or absence of particular experiences shape brain development in ways that are resistant to subsequent change. Brain regions/networks vulnerable at any given point in time tend to be those undergoing rapid development. In the perinatal period, depending upon the timing, dose, and duration of exposure, overall brain size, subcortical development, and connectivity between subcortical and cortical regions may be particularly vulnerable. 1 In con

“…Manuscripts from Golding and colleagues and Bertoldi and colleagues examine the lack of specificity of associations with regard to both domain and timing of neurodevelopmental assessment implying that what is measured and when it is measured matter . Tovo‐Rodrigues and colleagues include a binary outcome, to better align with neurodevelopmental diagnoses and report no association. Lastly, Rifas‐Shiman and colleagues observe poorer executive function and behaviour scores for acetaminophen exposure and even worse scores associated with ibuprofen exposure (for some comparisons), which leads to an entirely new conversation regarding risks if recommendations were made to switch analgesics.…”

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confidence: 99%

Prenatal exposure to acetaminophen and neurodevelopment

Parker

Werler

2020

Over-the-counter analgesic medications, including acetaminophen, ibuprofen, and aspirin, are the most commonly used medications among pregnant women. Over time, specific analgesic agents have been reported to increase risks of adverse fetal and child health outcomes, prompting recommendations and influencing trends in use. For example, aspirin was the most commonly used analgesic during pregnancy in the 1970s; but, following reports that late pregnancy use increased risks of fetal intracranial haemorrhage, use substantially declined in the 1980s. Use of acetaminophen increased simultaneously and, for the past four decades, is prevalent in approximately 60% of pregnant women in the United States. Since ibuprofen's introduction to the over-the-counter market in 1984, its use has also increased. 1 When considering the safety of medication use during pregnancy, most attention has been given to studies that focus on proximal outcomes, including spontaneous abortion, congenital malformations, and fetal growth and gestational length. More distal outcomes, such as measures of neurodevelopment among offspring, have recently been explored, due to researchers harnessing the power of registry-based data and long-standing birth cohorts.Over the past decade, many studies have reported adverse associations between prenatal exposure to acetaminophen and neurodevelopmental outcomes, specifically hyperactivity and attention behaviour disorders. In 2017, the Society of Maternal Fetal Medicine released a statement acknowledging the accruing body of evidence, yet concluded that the "weight of the evidence regarding a causal relationship is inconclusive." 2 This lack of certainty reflects the complexity of measuring causal effects of acetaminophen exposure on neurodevelopmental outcomes in observational studies. This special issue of Paediatric and Perinatal Epidemiology contributes an additional 8 manuscripts on the topic of prenatal exposure to acetaminophen in relation to neurodevelopment and aims to further our understanding of the association. It also brings to light the challenges of conducting observational studies on this topic and the corresponding vulnerability to systematic error. In this issue, Bandoli and colleagues 3 present the descriptive epidemiology of acetaminophen users. They show users have a higher prevalence of mental health co-morbidities, implying the results from studies that have not controlled for such factors may be confounded. Corroborating the descriptive epidemiology, Masarwa and colleagues 4 undertook a quantitative bias analysis to address this topic and conclude that previously observed associations may be explained by unmeasured confounding, specifically by parental ADHD and maternal migraine. The remaining six original manuscripts include data from populations in the United States, United Kingdom, Brazil, and Norway and are aimed primarily at examining associations between prenatal exposure to acetaminophen and varying measures of neurodevelopment, while also addressing potential biases. For exampl...