Backes CH, Hill KD, Shelton EL, Slaughter JL, Lewis TR, Weisz DE, et al. Patent ductus arteriosus: a contemporary perspective for the pediatric and adult cardiac care provider. J Am Heart Assoc. 2022;11:e025784.
Semberova J, Sirc J, Miletin J, Kucera J, Berka I, Sebkova S, et al. Spontaneous closure of patent ductus arteriosus in infants ≤1500 g. Pediatrics. 2017;140:e20164258.
Benitz WE. Committee on Fetus and Newborn, American Academy of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics. 2016;137. https://doi.org/10.1542/peds.2015-3730.
Nelson RJ, Thibeault DW, Emmanouilides GC, Lippmann M. Improving the results of ligation of patent ductus arteriosus in small preterm infants. J Thorac Cardiovasc Surg. 1976;71:169–78.
Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011;128:e1618–e1621.
Manalastas M, Zaheer F, Nicoski P, Weiss MG, Amin S. Acetaminophen therapy for persistent patent ductus arteriosus. NeoReviews. 2021;22:e320–e331.
Stark A, Smith PB, Hornik CP, Zimmerman KO, Hornik CD, Pradeep S, et al. Medication use in the neonatal intensive care unit and changes from 2010 to 2018. J Pediatr. 2022;240:66–71.e4.
Al-Turkait A, Szatkowski L, Choonara I, Ojha S. Drug utilisation in neonatal units in England and Wales: a national cohort study. Eur J Clin Pharm. 2022;78:669–77.
Gouyon 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 (2017-8). An inventory for future research. PLOS One. 2019;14:e0222667.
Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson 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;39:599–607.
Dani 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;135:16–22.
Mukherjee 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;106:113–4.
Dowd LA, Wheeler BJ, Al-Sallami HS, Broadbent RS, Edmonds LK, Medlicott NJ. Paracetamol treatment for patent ductus arteriosus: practice and attitudes in Australia and New Zealand. J Matern Fetal Neonatal Med. 2019;32:3039–44.
Jasani B, Mitra S, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2022, https://doi.org/10.1002/14651858.CD010061.pub5.
Jasani B, Weisz DE, McNamara PJ. Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants. Semin Perinatol. 2018;42:243–52.
Squires RH. Acute liver failure in children. Semin Liver Dis. 2008;28:153–66.
Lee WS, McKiernan P, Kelly DA. Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom. J Pediatr Gastroenterol Nutr. 2005;40:575–81.
Squires RH, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148:652–658.e2.
Wright CJ. Acetaminophen and the developing lung: could there be lifelong consequences? J Pediatr. 2021;235:264–276.e1.
McCulley DJ, Jensen EA, Sucre JMS, McKenna S, Sherlock LG, Dobrinskikh E, et al. Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures. Am J Physiol Lung Cell Mol Physiol. 2022;323:L1–L13.
Pacifici GM, Allegaert K. Clinical pharmacology of paracetamol in neonates: a review. Curr Ther Res. 2015;77:24–30.
McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30:2174–87.
Ramachandran A, Jaeschke H. Acetaminophen toxicity: novel insights into mechanisms and future perspectives. Gene Expr. 2018;18:19–30.
Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol. 2016;4:131–42.
Sandoval J, Orlicky DJ, Allawzi A, Butler B, Ju C, Phan CT, et al. Toxic acetaminophen exposure induces distal lung ER stress, proinflammatory signaling, and emphysematous changes in the adult murine lung. Oxid Med Cell Longev. 2019;2019:1–15.
Lee WM. Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away? J Hepatol. 2017;67:1324–31.
Robinson JF, Hamilton EG, Lam J, Chen H, Woodruff TJ. Differences in cytochrome p450 enzyme expression and activity in fetal and adult tissues. Placenta. 2020;100:35–44.
Sadler NC, Nandhikonda P, Webb-Robertson B-J, Ansong C, Anderson LN, Smith JN, et al. Hepatic cytochrome p450 activity, abundance, and expression throughout human development. Drug Metab Dispos. 2016;44:984–91.
Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharm Ther. 2008;118:250–67.
Hart SN, Cui Y, Klaassen CD, Zhong X. Three patterns of cytochrome P450 gene expression during liver maturation in mice. Drug Metab Dispos. 2009;37:116–21.
Xu S-F, Hu A-L, Xie L, Liu J-J, Wu Q, Liu J. Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats. PeerJ. 2019;7:e7429.
Green MD, Shires TK, Fischer LJ. Hepatotoxicity of acetaminophen in neonatal and young rats. I. Age-related changes in susceptibility. Toxicol Appl Pharm. 1984;74:116–24.
Hart JG, Timbrell JA. The effect of age on paracetamol hepatotoxicity in mice. Biochem Pharm. 1979;28:3015–7.
Oesch F, Fabian E, Landsiedel R. Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models. Arch Toxicol. 2019;93:3419–89.
Hukkanen J, Pelkonen O, Hakkola J, Raunio H. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol. 2002;32:391–411.
Hart SG, Cartun RW, Wyand DS, Khairallah EA, Cohen SD. Immunohistochemical localization of acetaminophen in target tissues of the CD-1 mouse: correspondence of covalent binding with toxicity. Fundam Appl Toxicol J Soc Toxicol. 1995;24:260–74.
Placke ME, Wyand DS, Cohen SD. Extrahepatic lesions induced by acetaminophen in the mouse. Toxicol Pathol. 1987;15:381–7.
Jeffery EH, Haschek WM. Protection by dimethylsulfoxide against acetaminophen-induced hepatic, but not respiratory toxicity in the mouse. Toxicol Appl Pharm. 1988;93:452–61.
Gu J, Cui H, Behr M, Zhang L, Zhang Q-Y, Yang W, et al. In vivo mechanisms of tissue-selective drug toxicity: effects of liver-specific knockout of the NADPH-cytochrome P450 reductase gene on acetaminophen toxicity in kidney, lung, and nasal mucosa. Mol Pharm. 2005;67:623–30.
Neff SB, Neff TA, Kunkel SL, Hogaboam CM. Alterations in cytokine/chemokine expression during organ-to-organ communication established via acetaminophen-induced toxicity. Exp Mol Pathol. 2003;75:187–93.
Bartolone JB, Beierschmitt WP, Birge RB, Hart SG, Wyand S, Cohen SD, et al. Selective acetaminophen metabolite binding to hepatic and extrahepatic proteins: an in vivo and in vitro analysis. Toxicol Appl Pharm. 1989;99:240–9.
Chen TS, Richie JP, Lang CA. Life span profiles of glutathione and acetaminophen detoxification. Drug Metab Dispos Biol Fate Chem. 1990;18:882–7.
Micheli L, Cerretani D, Fiaschi AI, Giorgi G, Romeo MR, Runci FM. Effect of acetaminophen on glutathione levels in rat testis and lung. Environ Health Perspect. 1994;102:63–64.
Bulera SJ, Cohenb SD, Khairallah EA. Acetaminophen-arylated proteins are detected in hepatic subcellular fractions and numerous extra-hepatic tissues in CD-1 and C57B1/6J mice. Toxicology. 1996;109:85–99.
Dimova S, Hoet PHM, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. Int J Biochem Cell Biol. 2005;37:1727–37.
Dimova S, Hoet PH, Nemery B. Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro. Biochem Pharm. 2000;59:1467–75.
Nassini R, Materazzi S, Andrè E, Sartiani L, Aldini G, Trevisani M, et al. Acetaminophen, via its reactive metabolite N -acetyl- p -benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 2010;24:4904–16.
Dobrinskikh E, Al-Juboori SI, Zarate MA, Zheng L, De Dios R, Balasubramaniyan D, et al. Pulmonary implications of acetaminophen exposures independent of hepatic toxicity. Am J Physiol Lung Cell Mol Physiol. 2021;321:L941–L953.
Breen K, Wandscheer JC, Peignoux M, Pessayre D. In situ formation of the acetaminophen metabolite covalently bound in kidney and lung. Supportive evidence provided by total hepatectomy. Biochem Pharm. 1982;31:115–6.
Dobrinskikh E, Sherlock LG, Orlicky DJ, Zheng L, De Dios R, Balasubramaniyan D, et al. The developing murine lung is susceptible to acetaminophen toxicity. Am J Physiol Lung Cell Mol Physiol. 2021;320:L969–L978.
LungMAP – Home. https://www.lungmap.net/. Accessed 4 Mar 2023.
Xie T, Wang Y, Deng N, Huang G, Taghavifar F, Geng Y, et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 2018;22:3625–40.
Negretti NM, Plosa EJ, Benjamin JT, Schuler BA, Habermann AC, Jetter CS, et al. A single-cell atlas of mouse lung development. Dev Camb Engl. 2021;148:dev199512.
Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996;85:863–73.
Li R, Li X, Hagood J, Zhu M-S, Sun X. Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface. J Clin Invest. 2020;130:2859–71.
Li C, Li M, Li S, Xing Y, Yang C-Y, Li A, et al. Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. Stem Cells. 2015;33:999–1012.
Lindahl P, Karlsson L, Hellström M, Gebre-Medhin S, Willetts K, Heath JK, et al. Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Dev Camb Engl. 1997;124:3943–53.
Gouveia L, Betsholtz C, Andrae J. Expression analysis of platelet-derived growth factor receptor alpha and its ligands in the developing mouse lung. Physiol Rep. 2017;5:e13092.
Soriano P. The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Dev Camb Engl. 1997;124:2691–2700.
Li R, Bernau K, Sandbo N, Gu J, Preissl S, Sun X. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. eLife. 2018;7:e36865.
Du Y, Guo M, Whitsett JA, Xu Y. ‘LungGENS’: a web-based tool for mapping single-cell gene expression in the developing lung. Thorax. 2015;70:1092–4.
Du Y, Kitzmiller JA, Sridharan A, Perl AK, Bridges JP, Misra RS, et al. Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development. Thorax. 2017;72:481–4.
Du Y, Ouyang W, Kitzmiller JA, Guo M, Zhao S, Whitsett JA, et al. Lung gene expression analysis web portal version 3: lung-at-a-glance. Am J Respir Cell Mol Biol. 2021;64:146–9.
Bandoli G, Palmsten K, Chambers C. Acetaminophen use in pregnancy: examining prevalence, timing, and indication of use in a prospective birth cohort. Paediatr Perinat Epidemiol. 2020;34:237–46.
International Agency for Research on Cancer. Pharmaceutical drugs: views and experts opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon 17–24 Oct. 1989. Lyon: IARC; 1990.
Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet Gynecol. 1981;58:57S–62S.
Niederhoff H, Zahradnik HP. Analgesics during pregnancy. Am J Med. 1983;75:117–20.
Lubawy WC, Garrett RJ. Effects of aspirin and acetaminophen on fetal and placental growth in rats. J Pharm Sci. 1977;66:111–3.
Lambert GH, Thorgeirsson SS. Glutathione in the developing mouse liver—I. Biochem Pharm. 1976;25:1777–81.
Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag C-G, et al. Paracetamol use during pregnancy — a call for precautionary action. Nat Rev Endocrinol. 2021;17:757–66.
Statement on the use of acetaminophen for analgesia and fever in pregnancy. https://sogc.org/en/content/featured-news/Statement_on_the_use_of_acetaminophen.aspx?WebsiteKey=4d1aa07b-5fc4-4673-9721-b91ff3c0be30. Accessed 4 Mar 2023.
ACOG Response to Consensus Statement on Paracetamol Use During Pregnancy | ACOG. https://www.acog.org/news/news-articles/2021/09/response-to-consensus-statement-on-paracetamol-use-during-pregnancy. Accessed 5/9/2023.
Official ENTIS Position Statement: Paracetamol (acetaminophen, APAP) use in pregnancy – ENTIS. https://www.entis-org.eu/entis-news/official-entis-position-statement-paracetamol-acetaminophen-apap-use-in-pregnancy. Accessed 4 Mar 2023.
Shaheen SO. Paracetamol use in pregnancy and wheezing in early childhood. Thorax. 2002;57:958–63.
Shaheen SO, Sterne JA, Songhurst CE, Burney PG. Frequent paracetamol use and asthma in adults. Thorax. 2000;55:266–70.
Newson RB, Shaheen SO, Chinn S, Burney PG. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J. 2000;16:817–23.
Fan G, Wang B, Liu C, Li D. Prenatal paracetamol use and asthma in childhood: a systematic review and meta-analysis. Allergol Immunopathol. 2017;45:528–33.
Sakulchit T, Goldman RD. Acetaminophen use and asthma in children. Can Fam Physician Med Fam Can. 2017;63:211–3.
Singh M, Varukolu S, Chauhan A, Jaiswal N, Pradhan P, Mathew JL, et al. Paracetamol exposure and asthma: what does the evidence say? An overview of systematic reviews. Pediatr Pulmonol. 2021;56:3189–99.
Kluckow M, Carlisle H, Broom M, Woods P, Jeffery M, Desai D, et al. A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus. J Perinatol. 2019;39:102–7.
Davidson JM, Ferguson J, Ivey E, Philip R, Weems MF, Talati AJ. A randomized trial of intravenous acetaminophen versus indomethacin for treatment of hemodynamically significant PDAs in VLBW infants. J Perinatol. 2021;41:93–99.
Schindler T, Smyth J, Bolisetty S, Michalowski J, Mallitt K-A, Singla A, et al. Early PARacetamol (EPAR) trial: a randomized controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants. Neonatology. 2021;118:274–81.
Hochwald O, Mainzer G, Borenstein-Levin L, Jubran H, Dinur G, Zucker M, et al. Adding paracetamol to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a double-blind, randomized, placebo-controlled pilot study. Am J Perinatol. 2018;35:1319–25.
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014;164:510–514.e1.
Patel R, Sushko K, van den Anker J, Samiee-Zafarghandy S. Long-term safety of prenatal and neonatal exposure to paracetamol: a systematic review. Int J Environ Res Public Health. 2022;19:2128.
Luecke CM, Liviskie CJ, Zeller BN, Vesoulis ZA, McPherson C. Acetaminophen for patent ductus arteriosus in extremely low-birth-weight neonates. J Pediatr Pharm Ther. 2017;22:461–6.
Sehgal A, Nitzan I, Krishnamurthy MB, Pharande P, Tan K. Toward rational management of patent ductus arteriosus: ductal disease staging and first line paracetamol. J Matern Fetal Neonatal Med. 2021;34:3940–5.
Mashally S, Nield LE, McNamara PJ, Martins FF, El-Khuffash A, Jain A, et al. Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus. J Thorac Cardiovasc Surg. 2018;156:1937–44.
Karabulut B, Paytoncu S. Efficacy and safety of oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants. Pediatr Drugs. 2019;21:113–21.
Vaidya R, Wilson D, Paris Y, Madore L, Singh R. Use of acetaminophen for patent ductus arteriosus treatment: a single center experience. J Matern Fetal Neonatal Med. 2020;33:2723–9.
Kimani S, Surak A, Miller M, Bhattacharya S. Use of combination therapy with acetaminophen and ibuprofen for closure of the patent ductus arteriosus in preterm neonates. Paediatr Child Health. 2021;26:e177–e183.
Okulu E, Erdeve O, Arslan Z, Demirel N, Kaya H, Gokce IK, et al. An observational, prospective, multicenter, registry-based cohort study comparing conservative and medical management for patent ductus arteriosus. Front Pediatr. 2020;8:434.
Cakir U, Tayman C, Karacaglar NB, Beser E, Ceran B, Unsal H. Comparison of the effect of continuous and standard intermittent bolus paracetamol infusion on patent ductus arteriosus. Eur J Pediatr. 2021;180:433–40.
Balasubramanian H, Jain V, Bhalgat P, Parikh S, Kabra N, Mohan D, et al. Low dose paracetamol for management of patent ductus arteriosus in very preterm infants: a randomised non-inferiority trial. Arch Dis Child Fetal Neonatal Ed. 2023;108:130–5.
Gover A, Levy PT, Rotschild A, Golzman M, Molad M, Lavie-Nevo K, et al. Oral versus intravenous paracetamol for patent ductus arteriosus closure in preterm infants. Pediatr Res. 2022;92:1146–52.
Murphy C, Bussmann N, Staunton D, McCallion N, Franklin O, EL-Khuffash A. The effect of patent ductus arteriosus treatment with paracetamol on pulmonary vascular resistance. J Perinatol. 2022;42:1697–8.
Torres-Cuevas I, Parra-Llorca A, Sánchez-Illana A, Nuñez-Ramiro A, Kuligowski J, Cháfer-Pericás C, et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674–81.
Berkelhamer SK, Farrow KN. Developmental regulation of antioxidant enzymes and their impact on neonatal lung disease. Antioxid Redox Signal. 2014;21:1837–48.
Flint RB, Roofthooft DW, van Rongen A, van Lingen RA, van den Anker JN, 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;82:678–84.
Abadier M, Wong A, Stathakis P, Singsit J, Pillay M, Graudins A. A case of accidental neonatal paracetamol overdose with prolonged half-life and measured metabolites. Clin Toxicol. 2019;57:1154–6.
Chiewa A, Buckleyb N, Paoc LT, Robertsd D. Pharmacokinetics of acetaminophen and metabolites after accidental acute overdose in a neonate. North American Congress of Clinical Toxicology (NACCT) Abstracts 2018. Clin Toxicol. 2018;56:951–2.
Juujärvi S, Saarela T, Pokka T, Hallman M, Aikio O. Intravenous paracetamol for neonates: long-term diseases not escalated during 5 years of follow-up. Arch Dis Child Fetal Neonatal Ed. 2021;106:178–83.
Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04459117. Accessed 4 Mar 2023.
Canadian National PDA Treatment Study – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04347720. Accessed 4 Mar 2023.