Prenatal exposure to acetaminophen and neurodevelopment

Abstract

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...

Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies

“…However, in a reverse experiment observing the effects of olanzapine co-treatment on transfer of other medications, paracetamol and valproate transfer across the placenta was increased following olanzapine combination therapy (unpublished work, Huang et al , 2023 in preparation). These increases in fetal drug exposure with co-treatment could be of clinical concern due to recent controversies surrounding paracetamol’s safety during pregnancy ( Masarwa et al , 2020 ; Parker and Werler, 2020 ), while valproate is a known teratogen ( Tomson et al , 2018 ; Abou-Khalil, 2019 ; Vajda et al , 2012 ).…”

Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies

“…However, in a reverse experiment observing the effects of olanzapine co-treatment on transfer of other medications, paracetamol and valproate transfer across the placenta was increased following olanzapine combination therapy (unpublished work, Huang et al, 2023 in preparation). These increases in fetal drug exposure with co-treatment could be of clinical concern due to recent controversies surrounding paracetamol's safety during pregnancy (Masarwa et al, 2020;Parker and Werler, 2020), while valproate is a known teratogen (Tomson et al, 2018;Abou-Khalil, 2019;Vajda et al, 2012).…”

Paediatric and Perinatal Epidemiology: Past, present and future

“… Acetaminophen and neurodevelopment 1 (co‐edited by Samantha Parker and Martha Werler), published in May 2020 Maternal health 2 (co‐edited by KS Joseph and Marian Knight), published in July 2020 Leveraging technology 3 (co‐edited by Courtney Lynch and Lauren Wise), published in September 2020 …”