Urinary acetaminophen metabolites and clinical outcomes in premature infants

BACKGROUND Extremely premature infants are treated with acetaminophen (APAP) for discomfort and patent ductus arteriosus. A recent study found an association between APAP metabolite levels in mothers’ breast milk and the diagnoses of both bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in their infants. METHODS Urine samples from 314 infants <29 weeks gestation in the TOLSURF and PROP studies were analyzed by untargeted UHPLC:MS/MS. We performed multivariate logistic regression and meta-analysis to examine associations between APAP metabolite levels and clinical outcomes. RESULTS 4-APAP sulfate was the highest detected and most abundant metabolite of 8 detected and was present in 98% of urines. In longitudinal studies (day 6-56), periods of elevated urinary 4-APAP-sulfate occurred in 24 of 28 infants and were of longer duration (10.1 vs 4.2 days, p=0.004) and higher levels (13.3 vs 5.6, p=0.013) in infants on enteral vs total parenteral nutrition. At both day 10 and 28 there were no significant associations between levels of APAP metabolites and BPD or ROP in all infants or only those on TPN or enteral feeds. CONCLUSION In two cohorts of premature infants, APAP metabolites were detected uniformly and levels were not associated with increased risk for two adverse clinical outcomes. Impact Statement ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01022580 ### Funding Statement M.G. is a recipient of a Howard Hughes Medical Institute Gilliam Fellowship, Achievement Award for College Scientists Foundation Scholarship, and a UCSF Discovery Fellows Program Award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board, University of California, San Francisco I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. * BPD : bronchopulmonary dysplasia ROP : retinopathy of prematurity APAP : acetaminophen UHPLC-MS/MS : ultrahigh performance liquid chromatography-mass spectrometry TPN : total parenteral nutrition