Paracetamol use during pregnancy — a call for precautionary action

Bauer, Ann Z.; Swan, Shanna H.; Kriebel, David; Liew, Zeyan; Taylor, Hugh S.; Bornehag, Carl‐Gustaf; Martino‐Andrade, Anderson Joel; Olsen, Jørn; Jensen, Rigmor; Mitchell, Rod; Skakkebæk, Niels E.; Jégou, Bernard; Kristensen, David M.

doi:10.1038/s41574-021-00553-7

Cited by 115 publications

(81 citation statements)

References 158 publications

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“…Despite the findings presented here, there is a gap in the understanding of the link between prostaglandins and steroidogenesis. Use of NSAIDs and analgesic drugs may only partially involve prostaglandin inhibition in the Leydig cell and thereby may be disrupting steroidogenesis through additional mechanisms such as by inhibiting steroidogenic enzymes or inducing oxidative stress ( Kristensen et al, 2011 ; Kristensen et al, 2012 ; Dean et al, 2013 ; Kristensen et al, 2016 ; Bauer et al, 2021 ). Cell-type specific effects of these drugs on other testicular cell types must be considered as well, as the normal function of the testes relies on the coordinated efforts of all the cell types involved.…”

Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 99%

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.

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Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 99%

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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“…Our findings have implications for understanding the potential mechanism of acetaminophen toxicity on neurodevelopment and for potential shifts in guidelines for acetaminophen use during pregnancy. Driven by the growing number of research studies associating in utero acetaminophen exposure with adverse childhood outcomes, including neurodevelopmental outcomes, multiple researchers and doctors in a 2021 consensus statement called for the reassessment of the safety of acetaminophen use during pregnancy by U.S. and European regulators [61]. Further studies are needed to identify the potential pathways between perinatal acetaminophen exposure and fetal neurodevelopment as well as the long-term consequences of perinatal acetaminophen exposure.…”

Section: Strengths Limitations and Future Directionsmentioning

confidence: 99%

Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways

et al. 2021

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Oxidative stress mechanisms may explain associations between perinatal acetaminophen exposure and childhood attention-deficit hyperactivity disorder (ADHD). We investigated whether the changes in umbilical cord plasma amino acids needed to synthesize the antioxidant glutathione and in the oxidative stress biomarker 8-hydroxy-deoxyguanosine may explain the association between cord plasma acetaminophen and ADHD in the Boston Birth Cohort (BBC). Mother–child dyads were followed at the Boston Medical Center between 1998 and 2018. Cord plasma analytes were measured from archived samples collected at birth. Physician diagnoses of childhood ADHD were obtained from medical records. The final sample consisted of 568 participants (child mean age [SD]: 9.3 [3.5] years, 315 (52.8%) male, 248 (43.7%) ADHD, 320 (56.3%) neurotypical development). Cord unmetabolized acetaminophen was positively correlated with methionine (R = 0.33, p < 0.001), serine (R = 0.30, p < 0.001), glycine (R = 0.34, p < 0.001), and glutamate (R = 0.16, p < 0.001). Children with cord acetaminophen levels >50th percentile appeared to have higher risk of ADHD for each increase in cord 8-hydroxy-deoxyguanosine level. Adjusting for covariates, increasing cord methionine, glycine, serine, and 8-hydroxy-deoxyguanosine were associated with significantly higher odds for childhood ADHD. Cord methionine statistically mediated 22.1% (natural indirect effect logOR = 0.167, SE = 0.071, p = 0.019) and glycine mediated 22.0% (natural indirect effect logOR = 0.166, SE = 0.078, p = 0.032) of the association between cord acetaminophen >50th percentile with ADHD. Our findings provide some clues, but additional investigation into oxidative stress pathways and the association of acetaminophen exposure and childhood ADHD is warranted.

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“…The cautious stance of the regulatory authorities in the USA and Europe partially reflects the lack of safe alternatives to treat fever and pain in pregnant women. A very recently published consensus statement supported by 91 scientists, clinicians, and public health professionals recommends to implement specific actions to caution pregnant women at the beginning of pregnancy to forego paracetamol unless its use is medically indicated, to consult with a physician or pharmacist if they are uncertain whether its use is indicated and before using paracetamol on a long-term basis, and to minimize exposure by using the lowest effective dose for the shortest possible time [67].…”

Section: Paracetamol Use During Pregnancymentioning

confidence: 99%

Paracetamol (Acetaminophen) and the Developing Brain

Bührer

Endesfelder

Scheuer

et al. 2021

IJMS

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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.

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Paracetamol use during pregnancy — a call for precautionary action

Cited by 115 publications

References 158 publications

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways

Paracetamol (Acetaminophen) and the Developing Brain

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