Paracetamol, in a small scale meta analysis was also associated with 20–30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings. There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mothers paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time. Overdose
Overdoses of paracetamol, that is, taking more than the recommended maximum daily dose of paracetamol for healthy adults of three or four grams, can cause potentially fatal liver damage.Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.
NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it. Kidney failure is also a possible side effect. Interactions
Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax. The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed. Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital, primidone, isoniazid, and possibly St Johns wort. On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.