A common complication for very preterm (premature) or very small babies is a PDA (patent ductus arteriosus). PDA is an open channel between the lungs and heart. It should close after birth, but sometimes remains open because of the baby's premature stage of development. A PDA can lead to life-threatening complications. The usual treatment for PDA has been indomethacin or ibuprofen. Recently paracetamol (acetaminophen), a commonly used drug to treat fever or pain in children and infants, 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 attractive alternative for the closure of a PDA.
We identified two studies that enrolled 250 preterm infants and compared the effectiveness and safety of paracetamol versus ibuprofen in the treatment of a PDA in early life. The studies were conducted in Turkey and China.
When the results of the two studies were combined, the success rate for paracetamol to close a PDA was similar to that of ibuprofen. Adverse events were similar in both groups. However, in general the trends favoured infants who received paracetamol and additionally the adverse events were lower in the paracetamol group. Infants who were treated with paracetamol had a reduced duration of needing extra oxygen and a lower risk of hyperbilirubinaemia than those treated with ibuprofen.
Quality of the evidence:
Although the healthcare providers were not blinded to which drug the infants received (paracetamol versus ibuprofen) the quality of the studies was good.
Paracetamol appears to be a promising new 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.
Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, 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. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.
In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported.
To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for closure of a PDA in preterm or low-birth-weight infants.
We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google ScholarTM to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials.
We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤ 34 weeks postmenstrual age (PMA)).
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.
Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I2 = 0 % for RR and 23% for RD).
There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for 'duration for need of supplemental oxygen' (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160).