Graduate Student UCSF Benioff Children's Hospital San Francisco San Francisco, California, United States
Background: Many extremely premature infants are exposed in the NICU to acetaminophen (APAP) for analgesia and closure of patent ductus arteriosus (PDA). APAP exposure in utero may be associated with asthma, and Santoro et al (J Pediatr 2022) reported that levels of APAP and metabolites in breast milk were associated with bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in the infants. Objective: Identify APAP metabolites in infant urine and examine their relationship to enteral vs. TPN feeding and the occurrence of BPD, ROP and PDA. Design/Methods: Untargeted metabolomics (UHPLC/MS:MS, Metabolon, Inc.) was performed on urine samples at day 10 and 28 from 171 infants < 29 weeks from TOLSURF, 143 infants from PROP and from cord/maternal plasma of 12 premature infants. Metabolite detection and relative abundance were determined from area under the peak, and levels between samples after median normalization. Associations between APAP levels and outcomes were examined by univariate and multivariate logistic regression with meta-analysis. Results: Of 8 identified APAP metabolites, 4-APAP-sulfate was most abundant and was detected in 75% of cord/maternal samples and 98% of urine samples with a wide range of levels; relative abundance of urinary APAP and other APAP metabolites was < 20% of 4-APAP-sulfate. In longitudinal studies of 28 infants (day 6-56), periods of elevated (>2-fold of median) urinary 4-APAP-sulfate occurred in 24 infants (86%) and were of longer duration (10.1 vs 4.2 days, p=0.004) and higher (13.3 vs 5.6, p=0.013) in infants on enteral vs TPN nutrition with no apparent association with BPD. In both day-10 and day-28 urine samples there were no significant associations between APAP metabolites and BPD (Table), ROP or PDA (p>=0.05). Because of the reported associations of BPD and ROP with APAP metabolites in breast milk, we performed separate analyses at 28 days for infants on TPN vs enteral nutrition: there was no significant association with BPD by meta-analysis for infants on TPN (n=188) and one significant association at 28 days for infants on enteral feeds (n=126): 3-(methylthio)Ac sulfate (OR 0.91, CI 0.82/1.00, p=0.045, Table), indicating lower levels associated with BPD.
Conclusion(s): Most premature infants are exposed to APAP in utero from maternal use, in the NICU as routine treatment for discomfort and for closure of PDA, and intermittently at higher levels from breast milk after initiation of enteral feeds. In two cohorts of infants, greater exposure to APAP did not increase the risk for adverse clinical outcomes.
.png)