Aim To identify all the reported adverse events associated with ibuprofen use in preterm neonates for PDA closure and quantify the risk per 100 patients.

Methods We followed the Cochrane standards for conducting systematic reviews of adverse events.¹ Eight electronic databases [Embase, Medline, BNI, PubMed, Cochrane library, IPA, CINAHL, clinical trials.gov] were searched to identify relevant studies using a predetermined search strategy. Published conference abstracts, grey literature, and reference lists of the retrieved articles were also searched. All studies providing information on adverse events of ibuprofen in preterm neonates with PDA were included. Following quality assessment of the retrieved studies, meta-analysis was performed to pool the results from the RCTs using Rev man 5.3 software. Results of the observational studies are descriptively reported and analysed. Protocol registered in PROSPERO (CRD42018067600).

Results The complete adverse events systematic review includes 84 studies (38 RCTs, 10 case reports, 4 case series, 31 cohort studies and 1 case-control study). The majority of adverse events were captured in retrospective cohort studies. Gastrointestinal (GI) bleeding: Pooled results from RCTs that compared ibuprofen to placebo showed significant difference RR [95% CI]: 1.99[1.13, 3.50] favouring placebo. Similarly, compared to paracetamol, ibuprofen was also associated with an increased risk of GI bleeding RR [95% CI]: 7.00[1.91, 25.61]. There was no significant difference in GI bleeding when comparing ibuprofen to indomethacin RR [95% CI]; 0.98[0.48, 2.00]. Renal adverse events: Data from RCTs showed that ibuprofen had a significantly low risk of oliguria compared to indomethacin RR [95% CI]: 0.38[0.25, 0.56]. However, no difference in risk of oliguria was found when comparing ibuprofen to paracetamol RR [95% CI]: 2.16[0.91, 5.11]. Serum creatinine levels after ibuprofen treatment compared to placebo was reported by 4 RCTs with favourable results to placebo MD [95% CI]; 8.66 [5.17, 12.15]. The risk of adverse events per 100 patients who received ibuprofen from data from prospective studies was 8.9 for GI bleeding, 7.6–7.8 for oliguria, 5.2 for rise in serum creatinine and 2.6 for renal failure. Increase in serum creatinine after treatment was most commonly reported in retrospective cohort studies (460 cases out of 1786 adverse events). Nine cases of GI bleeding led to discontinuation of ibuprofen treatment.

Conclusion Our meta-analysis of the RCT data supported results of previous systematic reviews.^{2 3} Combined results from RCTs and prospective cohort studies in our review show that oliguria is the most commonly reported adverse event among the renal adverse events. However, the high number of rising serum creatinine after treatment from retrospective studies should also be considered when treating preterm neonates with ibuprofen for PDA. Paracetamol might be favoured as it associated with less risk of GI bleeding when compared to ibuprofen.

References

1. Loke Y.K, Price D., Herxheimer A., et.al. Systematic reviews of adverse effects: framework for a structured approach. BMC Med Res Methodol 2007 July 5;7:32.

2. Ohlsson A., Walia R., Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database of Systematic Reviews, 2015, Issue 2. Art. No.: CD003481. doi: 10.1002/14651858.CD003481.pub6

3. Ohlsson A., Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews, 2011, Issue 7. Art. No.: CD004213. doi:10.1002/14651858.CD004213.pub3Save