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. This is because the placenta delivers oxygen to the fetal blood supply. 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 around 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 the PDA remains open because of the baby's immature stage of development.

A PDA in preterm babies is associated with life-threatening complications. The usual treatment for PDA has been the medicines indomethacin or ibuprofen, which inhibit the production of prostaglandins and promote the closure of the PDA. Prostaglandins are chemical compounds made throughout the body (i.e. not in any one particular organ), particularly wherever soft tissues are damaged. Their production (or 'synthesis') plays a key role in healing processes. They are known to play an important role in keeping the ductus arteriosus open (or 'patent'), so lowering their production would encourage closure of the ductus arteriosus.

Recently, paracetamol (acetaminophen) – a commonly used medicine 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 clinical trials 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.

What did we want to find out?

How effective and safe is paracetamol, which has weak anti-inflammatory properties, compared with placebo (a substance with no active therapeutic effect), or no intervention, or non-steroidal anti-inflammatory medicines (indomethacin and ibuprofen), for closure of a PDA in preterm or low birth weight infants?

What did we do?

We searched for studies that looked at short-term (benefit and safety) and long-term (neurodevelopmental) effects of paracetamol used either alone or in combination with ibuprofen compared to ibuprofen, indomethacin, placebo, or no intervention for prevention or treatment of a significant PDA in preterm or small babies. We subclassified treatment into early (< 14 days of age) and late (≥ 14 days of age) treatment.

What did we find? 

We identified 27 studies that enrolled 2278 preterm infants. These studies compared the efficacy and safety of paracetamol alone or in combination with ibuprofen versus ibuprofen, indomethacin, placebo, or no intervention for preventive treatment (prophylaxis) or treatment of a PDA. We identified 24 ongoing studies on this topic.

When the results of the included studies were combined, we found:

- the success rate for paracetamol to close a PDA was probably higher than that of placebo and likely similar to that of ibuprofen and indomethacin;
- paracetamol appears to have fewer harmful effects on the kidney and intestine;
- in two small studies that followed children to 24 months and five years of age, there was little to no difference in neurodevelopmental disability between the children given paracetamol and those given the non-experimental medicine or placebo.

For the key outcome of the closure of a PDA after the first course of treatment, we found:

- moderate-certainty evidence that there is probably little or no difference in effectiveness between paracetamol and ibuprofen; 
- low-certainty evidence that there is probably little or no difference in effectiveness between paracetamol and indomethacin; 
- low-certainty evidence that prophylactic paracetamol may be more effective than placebo/no intervention; 
- low-certainty evidence that early paracetamol treatment may be more effective than placebo/no intervention; 
- low-certainty evidence that there is probably little or no difference between late paracetamol treatment and placebo, 
- low-certainty evidence that there is probably little or no difference in effectiveness between the combination of ibuprofen plus paracetamol and ibuprofen alone.

The majority of infants included in these studies were of moderate preterm gestation. Thus, establishing the efficacy and safety of paracetamol for PDA treatment in extremely low gestational age babies (ELGANs: less than 28 weeks' gestation) or extremely low birth weight babies (ELBW: birth weight less than 1000 grams) requires further studies.

The healthcare providers were not always 'blinded' (unaware of which drug the infants received) in the studies. Thus, we judged the quality (certainty) of the evidence to be moderate or low.

How up to date is this evidence?

This review updates our previous review. The evidence is up to date to October 2021.