Persistent patent ductus arteriosus (PDA) is associated with increased neonatal morbidity, including necrotizing enterocolitis, bronchopulmonary dysplasia

and neurodevelopmental impairment. [1] Ibuprofen or indomethacin administered to pre term infants promote ductal closure, but these drugs are neither without side-ef fect, including renal, pulmonary, cerebral impairment while surgical closure its elf is also associated with poorer neurologic outcome. [2] Moreover, there are a lso contra-indications for ibuprofen or indomethacin administration. Consequentl y, there is a need for alternative treatments that result in better closure rate s or fewer adverse effects. A "serendipity" observation of Hammerman et al. rece ntly linked paracetamol exposure with PDA closure. [3] However, it should not be taken for granted yet that paracetamol induces PDA cl osure. If closure is driven by prostaglandin (PG) reduction, we should be aware that paracetamol has only very weak peripheral PG related effects and exerts its main effects (analgesia, fever reduction) through the central nervous system. [ 4],[5] Related to PG synthesis, paracetamol inhibits peroxidase (POX) (PGG2 to P GH2 conversion, POX) as one of its mechanisms of action. It hereby functions as a reducing co-substrate so that less PGG2 can be converted to PGH2 [Figure 1]. H owever, this inhibition is competitive with the PGG2 concentration itself and pe roxides (sources are white blood cells, thrombocytes = Not present in the centra l nervous system). Consequently, the peripheral PGH2 inhibition of PGH2 producti on is very limited and the pharmacological link between paracetamol exposure and systemic PG reduction related PDA closure is very weak. [4],[5] Figure 1: The arachidonic acid pathway, with specific emphasis on the interacti on of paracetamol (inhibiting) or endogenous compounds (hydroperoxide, PGG2, sti mulating) at the peroxidase enzyme Click here to view However, we believe in the relevance of serendipity, with sildenafil for pulmon ary hypertension and propranolol to treat hemangiomata of infancy as two recent illustrations of the clinical benefit of such observations. Despite the availabl e data on their clinical benefit, the administration of these compounds for thes e indications is still offlabel and unlicensed. Related to paracetamol for PDA c losure however, we urgently need a shift from a serendipity driven practice towa rd evidence based medicine. This includes pharmacokinetics, effectiveness and sa fety. At present, we know that an association between paracetamol exposure (60 m g/kg/24 h, 2-7 days, either oral or intravenous) and closure of the PDA has been reported. Including the six cases currently reported, observations in a still l imited number (n<50) of (extreme) preterm neonates are available, but none were included in prospective or comparative studies. [5],[6] Moreover, there are data on paracetamol pharmacokinetics and safety, but these data were based on lower dosing regimens (20-40 mg/kg/24 h, 1-2 days) and were collected in more mature n eonates. [7],[8] Consequently, we do not have subpopulation specific pharmacokin etics, nor safety data. Finally, we are unaware of any median paracetamol concen tration to aim for to induce closure of the ductus. Consequently, dose seeking s tudies and in vitro studies are needed to guide dosing. Serendipity is an important driver to further improve pharmacotherapy in neonate s. However, the next steps to further document the potential benefits of paracet amol or reject its claimed effects necessitates a more robust study design, that will include issues related to pharmacokinetics, effectiveness and safety.