The use of acetaminophen (paracetamol, APAP) in the neonatal intensive care unit (NICU) has become ubiquitous. Between 2005 and 2010, APAP was the 15th most common pharmacologic exposure among infants admitted to the Pediatrix-affiliated NICUs in the US.1Hsieh E.M. Hornik C.P. Clark R.H. Laughon M.M. Benjamin Jr., D.K. Smith P.B. et al.Medication use in the neonatal intensive care unit.Am J Perinatol. 2014; 31: 811-821Crossref PubMed Scopus (179) Google Scholar Over nearly the same period of time, a significant increase in the use of APAP was reported in German NICUs, occurring in 8.1% of all infants with very low birth weights by 2010.2Mehler K. Oberthuer A. Haertel C. Herting E. Roth B. Goepel W. et al.Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010.Eur J Pediatr. 2013; 172: 1633-1639Crossref PubMed Scopus (19) Google Scholar Since 2010, multiple reports indicate increasing APAP use in NICUs around the world. Data gathered in 2017-2018 from nearly 30 000 French infants showed that APAP was the third most commonly administered medication behind vitamin K and vitamin D and was given to >65% of all infants born at less than 27 weeks of gestation.3Gouyon B. Martin-Mons S. Iacobelli S. Razafimahefa H. Kermorvant-Duchemin E. Brat R. et al.Characteristics of prescription in 29 Level 3 Neonatal Wards over a 2-year period (2017-2018). An inventory for future research.PLoS One. 2019; 14: e0222667Crossref PubMed Scopus (3) Google Scholar It is likely that this rapid increase in APAP exposure is primarily driven by the desire to provide analgesia and limit opioid exposure. In fact, one French NICU reported that by 2012-2013, nearly 95% of patients in the NICU postsurgery were administered APAP.4Benahmed-Canat A. Plaisant F. Riche B. Rabilloud M. Canat G. Paret N. et al.Postsurgery analgesic and sedative drug use in a French neonatal intensive care unit: a single-center retrospective cohort study.Arch Pediatr. 2019; 26: 145-150Crossref PubMed Scopus (2) Google Scholar These data have been interpreted as demonstrating that “paracetamol is somehow a ‘rising star’ in NICU pain management.”5Allegaert K. A Critical review on the relevance of paracetamol for procedural pain management in neonates.Front Pediatr. 2020; 8: 89Crossref PubMed Scopus (0) Google Scholar The introduction of APAP into the NICU led to the chance observation that administration was temporally associated with closure of the patent ductus arteriosus (PDA).6Hammerman C. Bin-Nun A. Markovitch E. Schimmel M.S. Kaplan M. Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment.Pediatrics. 2011; 128: e1618-e1621Crossref PubMed Scopus (163) Google Scholar In the time since this case series was published in 2011, the rise in annual publications in PubMed.gov demonstrate the rapidly growing interest in this pharmacologic approach to PDA treatment (Figure 1). Multiple case series, cohort studies, and ultimately randomized controlled trials (RCTs) evaluating APAP for PDA followed, and these have been summarized in a number of comprehensive reviews.7Hamrick S.E.G. Sallmon H. Rose A.T. Porras D. Shelton E.L. Reese J. et al.Patent ductus arteriosus of the preterm infant.Pediatrics. 2020; 146: e20201209Crossref PubMed Scopus (1) Google Scholar, 8Su B.H. Lin H.Y. Chiu H.Y. Tsai M.L. Chen Y.T. Lu I.C. Therapeutic strategy of patent ductus arteriosus in extremely preterm infants.Pediatr Neonatol. 2020; 61: 133-141Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9Gillam-Krakauer M. Hagadorn J.I. Reese J. Pharmacological closure of the patent ductus arteriosus: when treatment still makes sense.J Perinatol. 2019; 39: 1439-1441Crossref PubMed Scopus (8) Google Scholar, 10Jasani B. Weisz D.E. McNamara P.J. Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants.Semin Perinatol. 2018; 42: 243-252Crossref PubMed Scopus (7) Google Scholar, 11Cuzzolin L. Bardanzellu F. Fanos V. The dark side of ibuprofen in the treatment of patent ductus arteriosus: could paracetamol be the solution?.Expert Opin Drug Metab Toxicol. 2018; 14: 855-868Crossref PubMed Scopus (5) Google Scholar, 12Bardanzellu F. Neroni P. Dessi A. Fanos V. Paracetamol in patent ductus arteriosus treatment: efficacious and safe?.Biomed Res Int. 2017; 2017: 1438038Crossref PubMed Scopus (28) Google Scholar, 13Allegaert K. Anderson B. Simons S. van Overmeire B. Paracetamol to induce ductus arteriosus closure: is it valid?.Arch Dis Child. 2013; 98: 462-466Crossref PubMed Scopus (58) Google Scholar Based on the available data, a 2020 Cochrane review by Ohlsson and Shah concluded that moderate-quality evidence demonstrated that APAP is as effective as ibuprofen to treat PDA.14Ohlsson A. Shah P.S. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.Cochrane Database Syst Rev. 2020; 1: CD010061PubMed Google Scholar However, this review also noted that the results from the more than 19 registered and ongoing trials are necessary before any “recommendations for the possible routine use of paracetamol in the newborn population can be made.” Specifically, the paucity of data regarding long-term neurodevelopmental outcome after early life APAP exposure was noted. Despite this conclusion, available clinical data indicate that neonatologists have readily adopted APAP for PDA closure. A 2017 survey done in the United Kingdom revealed 33% of NICUs were using APAP for PDA treatment,15Noureldein M. Hu K. Groucutt J. Heaver R. Gurusamy K. Paracetamol for patent ductus arteriosus in preterm infants: a UK national survey.J Matern Fetal Neonatal Med. 2020; : 1-4https://doi.org/10.1080/14767058.2020.1752652Crossref PubMed Scopus (3) Google Scholar increasing to 82% by 2020.16Mukherjee A. Jadhav V. Gupta A. Off-label use of paracetamol in managing patent ductus arteriosus across neonatal intensive care units in the UK.Arch Dis Child Fetal Neonatal Ed. 2021; 106: 113-114Crossref PubMed Scopus (0) Google Scholar Likewise, a 2017 survey of neonatologists in Australia revealed that >80% had prescribed APAP to treat PDA.17Dowd L.A. Wheeler B.J. Al-Sallami H.S. Broadbent R.S. Edmonds L.K. Medlicott N.J. Paracetamol treatment for patent ductus arteriosus: practice and attitudes in Australia and New Zealand.J Matern Fetal Neonatal Med. 2019; 32: 3039-3044Crossref PubMed Scopus (2) Google Scholar Furthermore, it appears that the burden of APAP exposure falls on the most immature newborn infants. An Italian study of 13 NICUs showed that between 2013 and 2017, APAP was used as a first-line agent in 47% of those born at 23-24 weeks of gestation and decreased to 24% of those born between 25 and 28 weeks18Dani C. Mosca F. Cresi F. Lago P. Lista G. Laforgia N. et al.Patent ductus arteriosus in preterm infants born at 23-24 weeks' gestation: Should we pay more attention?.Early Hum Dev. 2019; 135: 16-22Crossref PubMed Scopus (0) Google Scholar In the PDA-Tolerate trial (conducted between 2014 and 2017), APAP was chosen as first-line therapy for 26% (27/104) of those randomized to early treatment, and these infants were born at an average gestational age of 25.6 ± 1.5 weeks.19Liebowitz M. Kaempf J. Erdeve O. Bulbul A. Hakansson S. Lindqvist J. et al.Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320).J Perinatol. 2019; 39: 599-607Crossref PubMed Scopus (24) Google Scholar A large French study showed that in 2017-2018, APAP was used as the first-line agent in 10.5% of those treated for PDA, with an average gestational age of 26.4 ± 1.8 weeks.20Iacobelli S. Lorrain S. Gouyon B. Gambacorta S. Laforgia N. Gouyon J.B. et al.Drug exposure for PDA closure in France: a prospective, cohort-based, analysis.Eur J Clin Pharmacol. 2020; 76: 1765-1772Crossref PubMed Scopus (1) Google Scholar These data demonstrate that APAP is firmly established as a therapeutic option for a condition that disproportionately affects the most immature and vulnerable patients. Given the equipoise urged in the 2020 Cochrane review, it is pertinent to ask why neonatologists have rapidly adopted APAP to treat the PDA. Undoubtedly, the perception that APAP is safe has played a major role in this evolution. Multiple studies on the use of APAP for neonatal analgesia have demonstrated a favorable safety profile specifically related to hepatotoxicity.5Allegaert K. A Critical review on the relevance of paracetamol for procedural pain management in neonates.Front Pediatr. 2020; 8: 89Crossref PubMed Scopus (0) Google Scholar,21Pacifici G.M. Allegaert K. Clinical pharmacology of paracetamol in neonates: a review.Curr Ther Res Clin Exp. 2015; 77: 24-30Crossref PubMed Scopus (0) Google Scholar In addition, multiple reviews of APAP for PDA treatment have noted the robust safety profile with special regards to hepatotoxicity.10Jasani B. Weisz D.E. McNamara P.J. Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants.Semin Perinatol. 2018; 42: 243-252Crossref PubMed Scopus (7) Google Scholar, 11Cuzzolin L. Bardanzellu F. Fanos V. The dark side of ibuprofen in the treatment of patent ductus arteriosus: could paracetamol be the solution?.Expert Opin Drug Metab Toxicol. 2018; 14: 855-868Crossref PubMed Scopus (5) Google Scholar, 12Bardanzellu F. Neroni P. Dessi A. Fanos V. Paracetamol in patent ductus arteriosus treatment: efficacious and safe?.Biomed Res Int. 2017; 2017: 1438038Crossref PubMed Scopus (28) Google Scholar Even among the few Australian neonatologists who had not prescribed APAP for treatment of the PDA, less than 15% identified concerns about adverse effects or long-term outcomes as the reason for not prescribing, indicating a high level of confidence in APAP safety.17Dowd L.A. Wheeler B.J. Al-Sallami H.S. Broadbent R.S. Edmonds L.K. Medlicott N.J. Paracetamol treatment for patent ductus arteriosus: practice and attitudes in Australia and New Zealand.J Matern Fetal Neonatal Med. 2019; 32: 3039-3044Crossref PubMed Scopus (2) Google Scholar However, it must be acknowledged that at least for infants born at extremely low gestational ages (≤28 weeks), these conclusions appear to have been drawn prematurely. Studies of APAP for analgesia included very few subjects born at <32 weeks,21Pacifici G.M. Allegaert K. Clinical pharmacology of paracetamol in neonates: a review.Curr Ther Res Clin Exp. 2015; 77: 24-30Crossref PubMed Scopus (0) Google Scholar and studies of APAP for PDA closure have limitations due to small sample size, specifically in infants born at <28 weeks (see NICU Exposures: Underpowered to Determine Safety and Detect Harm, Not Reassuring). In adults, the majority of ingested APAP (80%-90%) is metabolized in the liver through glucuronidation by glucuronyl transferase or sulfation by sulfotransferases to nontoxic metabolites (Figure 2; available at www.jpeds.com).21Pacifici G.M. Allegaert K. Clinical pharmacology of paracetamol in neonates: a review.Curr Ther Res Clin Exp. 2015; 77: 24-30Crossref PubMed Scopus (0) Google Scholar, 22McGill M.R. Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis.Pharm Res. 2013; 30: 2174-2187Crossref PubMed Scopus (339) Google Scholar, 23Ramachandran A. Jaeschke H. Acetaminophen toxicity: novel insights into mechanisms and future perspectives.Gene Expr. 2018; 18: 19-30Crossref PubMed Scopus (0) Google Scholar, 24Yoon E. Babar A. Choudhary M. Kutner M. Pyrsopoulos N. 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With toxic APAP exposure, glucuronyl transferase and sulfotransferase activity is saturated and CYP2E1-generated NAPQI increases, ultimately depleting detoxifying glutathione stores. Accumulating NAPQI covalently binds to intracellular proteins, causing cellular dysfunction and death. In adults, pericentral hepatocytes express the greatest level of CYP2E1, leaving this cell population highly susceptible to NAPQI-induced injury. As noted, APAP has a robust safety profile, as defined by hepatoxicity in newborn infants. Even in cases of massive overdose, neonatal hepatotoxicity is rarely described.25Bucaretchi F. Fernandes C.B. Branco M.M. De Capitani E.M. Hyslop S. Caldas J.P. et al.Acute liver failure in a term neonate after repeated paracetamol administration.Rev Paul Pediatr. 2014; 32: 144-148Crossref PubMed Scopus (16) Google Scholar, 26Abadier M. Wong A. Stathakis P. Singsit J. Pillay M. Graudins A. 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Interestingly, at single-dose exposures similar to those used to close the PDA, infants born at an average gestational age of 28 weeks demonstrated significantly increased acetaminophen–cysteine and acetaminophen–mercapturate metabolites compared with adults.49Flint R.B. Roofthooft D.W. van Rongen A. van Lingen R.A. van den Anker J.N. van Dijk M. et al.Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.Pediatr Res. 2017; 82: 678-684Crossref PubMed Scopus (9) Google Scholar The authors of this study hypothesized that this metabolic profile could be explained by increased CYP2E1 metabolism and urged continued vigilance in monitoring for hepatic toxicity and NAPQI protein adducts when administering APAP in the preterm population. Similar metabolic profiles have been reported in case reports following APAP overdose in newborn infants, even in the absence of hepatotoxicity.49Flint R.B. 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