Ibuprofen for prevention of patent ductus arteriosus in preterm and/or low birth weight infants

Review question. Is prophylactic ibuprofen compared to placebo/no intervention or indomethacin effective and safe for prevention of PDA in preterm infants?

Background. Patent ductus arteriosus (PDA) is a common complication for very preterm (premature) or very small babies. PDA is an open vessel that channels blood from the lungs to the body. It should close after birth but sometimes remains open because of the baby's immature stage of development, and this can lead to life-threatening complications. Indomethacin is successful in causing PDA closure but can cause serious adverse effects. Another option is the drug ibuprofen, which can be given to prevent PDA.

Study characteristics. More than 1000 infants have been enrolled in trials of ibuprofen for prevention of a PDA; most studies were of small sample size.

Key results. Prophylactic use of ibuprofen reduces the incidence of patent ductus arteriosus (PDA), the need for rescue treatment with other medications, or the need for surgical closure. Adverse effects in the ibuprofen group compared to the placebo or no interventions group included significantly increased risk of kidney complications. Risk of digestive tract bleeding was increased with ibuprofen. Risk of intraventricular haemorrhage, or bleeding into the brain (grade II to IV), of borderline significance was reduced, but researchers reported no statistically significant differences in mortality, chronic lung disease at 28 days' or 36 weeks' postmenstrual age, necrotising enterocolitis, or time to reach full feeds. In the control group, the PDA had closed spontaneously by day 3 or 4 in 58% of neonates. Preventative treatment therefore exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefit for outcomes. No long-term follow-up studies have been published. Current evidence does not support the use of ibuprofen for prevention of PDA. A new approach for management of PDA is an early targeted treatment based on echocardiographic (ECG), or image of the heart, criteria within the first 72 hours of life; this has high sensitivity for diagnosing a PDA that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world.

Quality of evidence. This updated review of trials found that ibuprofen can prevent PDA but does not confer any other short-term or long-term benefits. The quality of evidence varied from low to high for different outcomes.

Authors' conclusions: 

This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended.

A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Read the full abstract...
Background: 

Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs.

Objectives: 

Primary objectives

To determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants.

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: 

Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants.

Data collection and analysis: 

We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence.

Main results: 

In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease.

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