The use of acetaminophen (paracetamol) for patent ductus arteriosus (PDA) closure in premature infants is steadily creeping into clinical practice. The vasoconstrictive effect of paracetamol on ductal tissue is achieved through inhibition of the peroxidase moiety of prostaglandin H2 synthase responsible for metabolising arachidonic acid (AA), thereby inhibiting prostaglandin production.1 Since the first report of its potential utility for PDA constriction by Hammerman et al. in 2011,2 there has been a steady stream of clinical trials and observational studies demonstrating the efficacy of acetaminophen in promoting ductal closure.3 Those studies have been a catalyst for its increasing use in the clinical field as a primary therapeutic intervention, when contra-indications to conventional non-steroidal anti-inflammatory drugs (NSAIDS, indomethacin and ibuprofen) exist, or following failure of closure after NSAIDS prior to referral for PDA ligation as a last ditch effort to avoid surgical intervention.

However, most of those clinical studies lack robust safety data for the use of acetaminophen in the premature population. In addition, those studies lack comprehensive monitoring of the cardiovascular system to enable the close study of the extra-cardiac physiologic consequences of acetaminophen-mediated PGE2 inhibition in the premature neonatal population. Liver toxicity associated with acetaminophen use remains a concern. A recent Cochrane review has highlighted the potential for adverse neurodevelopmental outcomes following antenatal and early postnatal exposure to acetaminophen and has called for the implementation of robust long-term follow-up to be integrated into any future trials.3 The link between early acetaminophen exposure and adverse neurodevelopmental outcome including autism spectrum disorder can be explained by the early depletion of the hepatic primary pathways for metabolising acetaminophen: glucuronidation and sulfation. “When the capacity to metabolise through the primary pathways is depleted or saturated, the fraction of the dose converted to reactive metabolites increases and the secondary metabolic pathways become increasingly involved”. Activation of secondary metabolic pathways can lead to oxidative stress resulting in neurotoxicity.4

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