Paracetamol crosses the placenta and the observed increased risk may be related to the limited capacity of the foetus to metabolize paracetamol. In adults, the main detoxification pathway of paracetamol is glucuronidation to the non-toxic metabolite glucuronide, while in the foetus the main metabolic pathway initially involves sulphation.
Glucuronidation consists of transfer of the glucuronic acid component of UDP -glucuronic acid to a substrate by any of several types of UDP -glucuronosyltransferase.
Glucuronidation starts at the 18th gestational week and increases until the 23rd week-a pattern that could be related to an increased risk from exposure in the first trimester. Metabolism of paracetamol to the highly reactive oxide N-acetyl-pbenzoquinoneimine (NAPQI), depends on the activity of the cytochrome P450 system and on Glutathione S Transferase (GST). In adults, cytochrome P450 enzymes metabolize 4–5% of the paracetamol to NAPQI, and this percentage increases when glucuronidation and sulphation are saturated. NAPQI is then detoxified by GST.
The expression of GST in the lung of the foetus progressively decreases after week 15 of gestation, and this could be related to an increase in risk from use of paracetamol in the third trimester. A paracetamol dose-dependent decrease in levels of the anti-oxidant glutathione in the lung has been proposed. Recent studies suggest that glutathione’s depletion in the lung may occur in relatively low doses. This may reduce the capacity to counteract the toxic effects of NAPQI and may affect the response to oxidative stress and possibly also to impaired antigen processing. Avoiding NSAID s may exert an effect on the lungs mediated by the lack of suppression of COX, an anti-inflammatory pathway that promotes prostaglandin E2 production in favour of T-helper type 2 response while inhibiting T-helper type I lymphocytes. This would promote an allergic tendency in the immune response to various antigenic stimuli. Yet, another possible mechanism is an immune-modulating IgE mediated effect of paracetamol as an antigenic agent,which would increase asthma provocation.