Review question: How effective and safe are paracetamol, which has weak anti-inflammatory properties, compared with placebo (a substance with no active therapeutic effect), or no intervention, or nonsteroidal anti-inflammatory drugs (indomethacin and ibuprofen), for closure of a PDA in preterm/low birth weight infants?

Background: A common complication for preterm (premature) or small babies is a patent ductus arteriosus (PDA). Blood circulation to the (as yet) non-functioning lungs is unnecessary before birth (the fetal blood supply is oxygenated via the placenta). The PDA is a temporary fetal blood vessel that connects the pulmonary artery (the vessel that, after birth, takes blood depleted of oxygen from the heart to the lungs) to the aorta (the vessel that takes freshly oxygenated blood, returned from the lungs to the heart by the pulmonary vein, away from the heart and on the beginning of its journey round the body). In other words the PDA ‘short-circuits’ the fetal circulation of blood through the lungs.. It is necessary to sustain life in the womb, but it should close after birth. Sometimes it remains open because of the baby’s immature stage of development. A PDA can lead to life-threatening complications. The usual treatment for PDA has been indomethacin or ibuprofen which inhibit the production of prostaglandins and promotes the closure of the PDA. Recently paracetamol (acetaminophen), a commonly used drug to treat fever or pain in infants, children and adults, has been suggested as an alternative to ibuprofen, with potentially fewer side effects. A number of case reports and case series have suggested that paracetamol may be an alternative for the closure of a PDA. Exactly how paracetamol works to close the PDA is not known, but probably involves inhibition of prostaglandin synthesis. Prostaglandins are chemical compounds which are made throughout the body (i.e. not in any one particular organ), particularly wherever soft tissues are damaged, and their production (synthesis) plays a key role in healing processes. They are known to play an important role in keeping the ductus arteriosus open (patent), so lowering their production would encourage closure of the ductus arteriosus.

Study characteristics: We identified a total of eight studies that enrolled 916 preterm infants and compared the effectiveness and safety of paracetamol versus ibuprofen, indomethacin or placebo in the treatment of a PDA in early life.

Key results: When the results of the included studies were combined, the success rate for paracetamol to close a PDA was higher than that of placebo and similar to that of ibuprofen and indomethacin. Paracetamol appears to have fewer adverse effects on kidney and liver functions. In one small study that followed children to 18 to 24 months of age there was no difference in neurodevelopmental impairment. The evidence is up to date as of November 2017.

Conclusions: Paracetamol appears to be a promising alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects.

Additional studies testing this intervention and including longer-term follow-up are needed before paracetamol can be recommended as standard treatment for a PDA in preterm infants. Several studies are ongoing that will eventually provide additional information. Because of reports of a possible association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood and language delay in girls, long-term follow-up to at least 18 to 24 months’ postnatal age must be incorporated in any studies of paracetamol in the newborn population.

Quality of evidence: Although the healthcare providers were not always ‘blinded‘ (unaware of which drug the infants received) we judged the quality of the evidence to be moderate.