Paracetamol (Acetaminophen) and the Developing Brain

Abstract

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.

Evaluation of the effects of overdose Acetaminophen toxicity in rats: Ozone, which can be preferred as a complementary therapy

“…Since NAPQI mainly tends to bind to structures containing the -SH group, NAPQI rapidly binds especially to cellular GSH while forming and is detoxified in this way. However, after excessive doses of APAP use, an excessive amount of NAPQI occurs in the cell, and when the decreased GSH levels cannot meet the increased amount of NAPQI, NAPQI, a reactive metabolite of APAP, binds to other -SH-containing cellular proteins, causing suppression of mitochondrial respiration and development of cellular damage [27,28,29].…”

Potential adverse actions of prenatal exposure of acetaminophen to offspring

“…As APAP can pass through the blood-brain barrier, it can act both centrally and peripherally through different molecular regulatory mechanisms. For example, one of the mechanisms of APAP action is thought to relieve pain is through competitive suppression of the peroxidase moiety of prostaglandin H2 synthase and regulation of cannabinoid receptor signaling pathway ( Bührer et al, 2021 ). Additionally, APAP has also been found to inhibit serotonergic mechanisms for relieving pain in clinical studies ( Pickering et al, 2008 ).…”

Acetaminophen causes neurodevelopmental injury in susceptible babies and children: no valid rationale for controversy

“…This summary statement called for increased awareness of the potential role of APAP in this phenomenon, but it was criticized heavily by the American College of Obstetricians and Gynecologists (ACOG). In its response [ 15 ], the ACOG concluded that available studies “show no clear evidence that proves a direct relationship between the prudent use of APAP during any trimester and fetal developmental issues.” The ACOG further concluded that “physicians should not change clinical practice until definitive prospective research is done.” Considering the ACOG response, it is important to note that evidence of APAP inducing neurodevelopmental problems during the prenatal period is concerning but limited [ 2 , 16 , 17 ]. As shown in Table 1 , only one of 20 lines of evidence was related only to the prenatal period.…”