EBNEO Commentary: Paracetamol/acetaminophen to avoid PDA ligation: How to interpret impact on 18- to 24-month outcomes.

Abstract

Mashally S, Banihani R, Jasani B, Nield LE, Martins FF, Jain A, Weisz DE. Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus? J Perinatol 2021; Aug 21; 1–7. Online ahead of print. PMID 34453113. Acetaminophen (APAP) use among ELBW infants is increasing worldwide.1, 2 There is an urgent need to evaluate both the safety and efficacy of APAP for PDA treatment. In this retrospective study, Mashally and colleagues have compared outcomes of ELGANS in which differing approaches across two epochs were used for the treatment of a persistent PDA (pPDA) at a single centre: surgical ligation and APAP with ligation after failed closure. Comparing the neurodevelopmental outcomes of these infants at 18–24 months corrected age, the authors found no difference in the risk of NDI or death between infants treated for a pPDA between the two epochs. They conclude that APAP is a safe and effective therapy for late treatment of the PDA to avoid surgical ligation. These results add to the growing body of literature evaluating the use of APAP for PDA treatment. However, a number of issues must be considered. Although the authors state that the objective was to evaluate the ‘association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA)’, this precise goal could not be met with the retrospective design and included subjects. Specifically, in epoch1 – the PDA ligation epoch – over 25% of the subjects did not undergo PDA ligation. In epoch2 – the APAP epoch – 20% were not exposed to APAP. Therefore, it is more accurate to state that this study compared outcomes across epochs with different prevailing clinical approaches to treatment of a late PDA. Furthermore, the small sample size also limits the ability to detect clinically relevant differences in outcomes. Larger observational and interventional studies that balance patient characteristics, avoid treatment contamination and minimise treatment selection bias are needed to determine the safety of APAP for pPDA. Lastly, any conclusion regarding the ‘safety’ of APAP must be considered in relation to the comparison therapy. In this study, the comparison was surgical ligation, which is an independent risk factor for poor neurodevelopmental outcomes.3 Given the risks of ligation, it could be argued that a pharmacologic approach that limits these exposures, and yet is not clearly safer, may potentially carry underappreciated risks that must be considered. The authors previously reported that late APAP exposure was associated with an increase in chronic lung disease.4 Although referenced in their methods, they do not comment further on this association here. The present report indicates that rates of moderate-severe bronchopulmonary dysplasia were 65% in epoch1 and 81% in epoch2 (p = 0.11). Although this difference did not reach statistical significance, a 16% absolute increase in the rates of this outcome is of possible clinical significance, particularly in the light of the reduced frequency of PDA ligation. This potential signal for harm, as well as the potential impact of APAP exposures on the developing lung, brain and endocrine function, reminds us that studies evaluating APAP safety should include broad measures of end-organ injury.5-7 With these points in mind, the conclusion regarding the safety of APAP should be regarded cautiously. URL LINK: URL TO THE FULL REVIEW ON THE EBNEO WEBSITE https://ebneo.org/apap-pda-ligation-18-24-month-outcomes None stated.