Prenatal acetaminophen exposure and neurodevelopment: State of the evidence

Talge, Nicole M.

doi:10.1111/ppe.12659

Cited by 6 publications

(3 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are, however, several points of concern [50,51]. First, the questionnaires used have poor internal and external validity, as they were developed as screening instruments rather than diagnostic tools.…”

Section: Paracetamol Use During Pregnancymentioning

confidence: 99%

Paracetamol (Acetaminophen) and the Developing Brain

Bührer

Endesfelder

Scheuer

et al. 2021

IJMS

View full text Add to dashboard Cite

Paracetamol is commonly used to treat fever and pain in pregnant women, but there are growing concerns that this may cause attention deficit hyperactivity disorder and autism spectrum disorder in the offspring. A growing number of epidemiological studies suggests that relative risks for these disorders increase by an average of about 25% following intrauterine paracetamol exposure. The data analyzed point to a dose–effect relationship but cannot fully account for unmeasured confounders, notably indication and genetic transmission. Only few experimental investigations have addressed this issue. Altered behavior has been demonstrated in offspring of paracetamol-gavaged pregnant rats, and paracetamol given at or prior to day 10 of life to newborn mice resulted in altered locomotor activity in response to a novel home environment in adulthood and blunted the analgesic effect of paracetamol given to adult animals. The molecular mechanisms that might mediate these effects are unknown. Paracetamol has diverse pharmacologic actions. It reduces prostaglandin formation via competitive inhibition of the peroxidase moiety of prostaglandin H2 synthase, while its metabolite N-arachidonoyl-phenolamine activates transient vanilloid-subtype 1 receptors and interferes with cannabinoid receptor signaling. The metabolite N-acetyl-p-benzo-quinone-imine, which is pivotal for liver damage after overdosing, exerts oxidative stress and depletes glutathione in the brain already at dosages below the hepatic toxicity threshold. Given the widespread use of paracetamol during pregnancy and the lack of safe alternatives, its impact on the developing brain deserves further investigation.

show abstract

Section: Paracetamol Use During Pregnancymentioning

confidence: 99%

Paracetamol (Acetaminophen) and the Developing Brain

Bührer

Endesfelder

Scheuer

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…A large body of evidence suggests the role of APAP overdose in neurodevelopmental impairment [15][16][17]. Nevertheless, few studies relate adult neurogenesis to paracetamol overdose toxicity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose

Suárez,

de Ceglia,

Rodríguez-Pozo

et al. 2024

IJMS

View full text Add to dashboard Cite

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood–brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.

show abstract

“…Commentaries included in this issue offer perspectives to aid readers’ interpretation of findings reported in this issue, many of which can be extended to the larger body of literature on prenatal exposure to acetaminophen and childhood outcomes. Commentaries by Wood and Talge review the manuscripts included in this issue and raise important points regarding the interpretation of findings. Wood draws our attention to the difficulty in understanding the magnitude of overall bias and the challenges of accounting for multiple biases that can occur within the same study.…”

mentioning

confidence: 99%

Prenatal exposure to acetaminophen and neurodevelopment

Parker

Werler

2020

Paediatric Perinatal Epid

View full text Add to dashboard Cite

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...

show abstract

Prenatal acetaminophen exposure and neurodevelopment: State of the evidence

Cited by 6 publications

References 11 publications

Paracetamol (Acetaminophen) and the Developing Brain

Paracetamol (Acetaminophen) and the Developing Brain

Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose

Prenatal exposure to acetaminophen and neurodevelopment

Contact Info

Product

Resources

About