Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants

Review question

Is the use of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitors, placebo or no intervention for closing a patent ductus arteriosus (PDA) safe and effective in improving the rate of ductal closure and other important clinical outcomes in preterm or low birth weight (or both) infants?

Background

A common complication for very preterm (premature) or very small babies is PDA. PDA is an open vascular channel between the lungs and the heart. It should close after birth, but sometimes remains open because of the baby's immature stage of development. PDA can lead to life-threatening complications. The usual treatment for PDA has been indomethacin, a medicine that will successfully close the PDA in the majority of babies, but can cause serious side effects. Another option is the drug ibuprofen.

Study characteristics

We searched scientific databases for randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) in preterm infants (born at less than 37 weeks into pregnancy), low birth weight (less than 2500 g) infants, or preterm and low birth weight infants with a PDA. The treatments were ibuprofen, indomethacin, another cyclo-oxygenase inhibitor, placebo or no treatment. The evidence is current to May 2014.

Results

This review of 33 trials (2190 infants) found that ibuprofen was as effective as indomethacin to close a PDA and caused fewer transient side effects on the kidneys and reduced the risk of necrotising enterocolitis, a serious condition that affects the gut. Whether ibuprofen confers any important long-term advantages on development is not known. Additional long-term follow-up studies to 18 months of age and to the age of school entry are needed to decide whether ibuprofen or indomethacin is the drug of choice for closing a PDA.

Authors' conclusions: 

Ibuprofen is as effective as indomethacin in closing a PDA and currently appears to be the drug of choice. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Oro-gastric administration of ibuprofen appears as effective as iv administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically guided versus standard iv ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

Read the full abstract...
Background: 

Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects.

Objectives: 

To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor, placebo or no intervention for closing a patent ductus arteriosus in preterm, low birth weight, or preterm and low birth weight infants.

Search strategy: 

We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, and www.abstracts2view.com/pas in May 2014.

Selection criteria: 

Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants.

Data collection and analysis: 

Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group.

Main results: 

We included 33 studies enrolling 2190 infants.

Two studies compared intravenous (iv) ibuprofen versus placebo (270 infants). In one study (134 infants) ibuprofen reduced the incidence of failure to close a PDA (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.51 to 0.99; risk difference (RD) -0.18, 95% CI -0.35 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 3 to 100). In one study (136 infants), ibuprofen reduced the composite outcome of infant mortality, infants who dropped out, or infants who required rescue treatment (RR 0.58, 95% CI 0.38 to 0.89; RD -0.22, 95% CI -0.38 to -0.06; NNTB 5, 95% CI 3 to 17). One study (64 infants) compared oral ibuprofen with placebo and noted a significant reduction in failure to close a PDA (RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4).

Twenty-one studies (1102 infants) reported failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 1.00, 95% CI 0.84 to 1.20; I2 = 0%; typical RD 0.00, 95% CI -0.05 to 0.05; I2 = 0%). The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (16 studies, 948 infants; typical RR 0.64, 95% CI 0.45 to 0.93; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 13 to 100; I2 = 0% for both RR and RD). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, 471 infants; mean difference (MD) -2.4 days, 95% CI -3.7 to -1.0; I2 = 19%).

Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) (seven studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen (four studies, 304 infants; typical RR 0.41, 95% CI 0.27 to 0.64; typical RD -0.21, 95% CI -0.31 to -0.12; NNTB 5, 95% CI 3 to 8). Transient renal insufficiency was less common in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen, early versus expectant administration of iv ibuprofen, echocardiographically guided iv ibuprofen treatment vs. standard iv ibuprofen treatment and continuous infusion of ibuprofen vs. intermittent boluses of ibuprofen and long-term follow-up were studied in too few trials to draw any conclusions.

Share/Save