EBNEO commentary: Patent ductus arteriosus (PDA)—To treat early or not with ibuprofen?

Patent ductus arteriosus (PDA) is common in extreme preterm infants,1 and its management is a subject of debate.2 A large PDA of more than 1.5 mm in diameter which is persistent beyond 3 days of age is associated with a higher mortality and morbidity as well as a greater risk of bronchopulmonary dysplasia.3 Systematic reviews of randomised, controlled trials showed that pharmacological treatment with ibuprofen-induced PDA closure had no beneficial effects on clinical outcomes.4, 5 Therefore, the pharmacological treatment of PDA in extreme preterm infants has decreased.6 However, the evidence to support this strategy is limited and contradictory.7 In the Baby-OSCAR trial, preterm infants between 23+0 weeks and 28+6 weeks, death or moderate or severe bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age occurred in 69.2% (220/318) infants in the ibuprofen group and 63.5% (202/318) in the placebo group (adjusted risk ratio: 1.09, 95% CI 0.98–1.20). This was statistically not significant. Subgroup analysis of primary outcome for each gestational age favours placebo group but none were statistically significant as numbers were small. Secondary outcomes like intraventricular haemorrhage, cystic periventricular leukomalacia, clinically significant pulmonary haemorrhage and discharge on home oxygen were higher in ibuprofen group but none of them were statistically significant. PDA closed or <1.5 mm in diameter at 3 weeks of age confirmed by echocardiography was 55.5% (176/317) in the ibuprofen group compared to 37% (117/316) in the placebo group (adjusted risk ratio, 1.50; 95% CI: 1.30–1.74). Open-label treatment including surgical ligation was 14.2% in the ibuprofen group and 29.8% in the placebo group. Even though in the ibuprofen group, more PDA closed or less than 1.5 mm in diameter at 3 weeks of age, no improvement in the primary outcome was observed. The limitations of the trial were, not meeting the enrolment goal of 730 infants because of non-availability of drugs, changes in the clinical practice and effect of COVID-19 pandemic. Although early assessment for randomization was encouraged, first dose of ibuprofen or a placebo was administered at a median of 61 h after birth. This trial did not target haemodynamically significant PDA identified by clinical findings, rather than those screened by echocardiography. Other important limitation was, in spite of strict criteria, open-label therapy was received in 29.8% in the placebo group which made it more difficult to identify between-group differences in clinical outcomes. Despite above limitations, the Baby-OSCAR trial is the largest study on early pharmacological treatment of PDA using strict echocardiography screening criteria to diagnose haemodynamically significant PDA. Recently published Beneductus trial in similar gestational age group and comparable primary and secondary outcomes as the Baby-OSCAR trial showed expected management of PDA noninferior to early management with ibuprofen.8 Cochrane reviews published in 2020 on ibuprofen as a prevention of PDA and treatment of PDA concluded that ibuprofen closes PDA but did not benefit short-term or long-term outcomes.9 To conclude, in extreme preterm infants with large PDA, there is no evidence that early treatment with ibuprofen would reduce the risk of death or moderate or severe BPD at 36 weeks postmenstrual age. It is plausible that an attempt to close the PDA with ibuprofen may be more harmful than the condition itself. Ibuprofen has potential adverse effects and there are no proven clinical benefits. So, clinicians should avoid using it for early treatment of PDA. URL LINK: https://ebneo.org/ebneo-commentary-pda-ibuprofen-or-not Rashida Javed: Writing – original draft; methodology; writing – review and editing. Harsha Gowda: Conceptualization; methodology; validation; visualization; writing – review and editing; supervision. None. None.