To examine whether oral administration of paracetamol as a first-line agent had a greater effect on the closure of a patent ductus arteriosus than the intravenous route.
We performed a retrospective study of preterm infants (<37 weeks of gestation) between 2012 and 2020 treated with oral or intravenous paracetamol as the first line for patent ductus arteriosus (PDA) constriction and compared rates of ductal closure, course duration, cumulative dose, PDA characteristics, and serum levels.
Over the study period, 80 preterm infants received paracetamol, of which 50 received paracetamol as first-line treatment to augment constriction of the PDA. Closure rate was higher in the oral group (n = 15/19, 79%) compared to the intravenous group (n = 8/20, 40%, p < 0.01), and remained significant after adjusting for gestational age, length of treatment, and postnatal age (OR 0.14, 95% CI 0.03–0.67, p = 0.014, RR 0.51, 95% CI 0.28–0.91). Eleven preterm infants received a combination of both oral and intravenous paracetamol with a closure rate of 45% (n = 5).
Oral administration of paracetamol as a first-line agent is more efficacious to constrict the PDA than the intravenous route, irrespective of gestational age or course duration.
Our retrospective study comparing the use of oral versus intravenous paracetamol as the first line for patent ductus arteriosus (PDA) constriction in preterm infants demonstrates that oral administration of paracetamol is more efficacious to constrict the PDA than the intravenous route, irrespective of gestational age or course duration.
To our knowledge, this is the first published study (prospective or retrospective) to compare the efficacy of oral versus intravenous paracetamol as a first-line treatment for PDA closure in preterm infants.
Our finding may improve the rate of PDA closure when paracetamol is used as a first-line agent.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.15 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Noori, S. et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics 123, e138–e144 (2009).
Hamrick, S. E. et al. Patent ductus arteriosus of the preterm infant. Pediatrics 146, e20201209 (2020).
El-Khuffash, A., Levy, P. T., Gorenflo, M. & Frantz, I. D. 3rd The definition of a hemodynamically significant ductus arteriosus. Pediatr. Res. 85, 740–741 (2019).
Hammerman, C. et al. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 128, e1618–e1621 (2011).
Jasani, B., Weisz, D. E. & McNamara, P. J. Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants. Semin. Perinatol. 42, 243–252 (2018).
Ohlsson, A. & Shah, P. S. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 27, CD010061 (2020).
Terrin, G. et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch. Dis. Child Fetal Neonatal Ed. 101, F127–36 (2016).
Ferguson, J. M. Pharmacotherapy for patent ductus arteriosus closure. Congenit. Heart Dis. 14, 52–56 (2019).
Bin-Nun, A., Fink, D., Mimouni, F. B., Algur, N. & Hammerman, C. Paracetamol serum concentrations in neonates treated enterally for ductal closure: a pilot study. J. Pediatr. 198, 304–307 (2018).
El-Khuffash, A. et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr. Res. 76, 238–44 (2014).
Vaidya, R., Knee, A., Paris, Y. & Singh, R. Predictors of successful patent ductus arteriosus closure with acetaminophen in preterm infants. J. Perinatol. 41, 998–1006 (2021).
Ramos, F. G., Rosenfeld, C. R., Roy, L., Koch, J. & Ramaciotti, C. Echocardiographic predictors of symptomatic patent ductus arteriosus in extremely-low- birth-weight preterm neonates. J. Perinatol. 30, 535–9 (2010).
Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J. Pediatr. 92, 529–34 (1978).
Jobe, A. H. & Bancalari, E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med 163, 1723–9 (2001).
Bell, M. J. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 187, 1–7 (1978).
Allegaert, K., Palmer, G. M. & Anderson, B. J. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch. Dis. Child. 96, 575–80 (2011).
Sancak, S. et al. Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants? J. Matern. Fetal Neonatal Med. 29, 135–139 (2016).
Ohlsson, A., Walia, R. & Shah, S. S. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst. Rev. 11, CD003481 (2020).
Mitra, S. et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 319, 1221–1238 (2018).
Barzilay, B. et al. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 97, F116–9 (2012).
Pacifici, G. M. Clinical pharmacology of ibuprofen in preterm infants: a meta-analysis of published data. http://www.gnresearch.org/doi/10.5935/MedicalExpress.2014.02.02. Accessed 10 August 2020 (2014).
Anderson, B. J., Woollard, G. A. & Holford, N. H. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br. J. Clin. Pharmacol. 50, 125–134 (2000).
Valerio, E. et al. Intravenous paracetamol for PDA closure in the preterm: a single-center experience. Eur. J. Pediatr. 175, 953–966 (2016).
Terrin, G. et al. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital. J. Pediatr. 20, 21 (2014).
Oncel, M. Y. et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 103, 166–9 (2013).
Ghaderian, M., Barekatain, B. & Dardashty, A. B. Comparison of oral acetaminophen with oral ibuprofen on closure of symptomatic patent ductus arteriosus in preterm neonates. J. Res. Med. Sci. 24, 96 (2019).
Balachander, B. et al. Comparison of efficacy of oral paracetamol versus ibuprofen for PDA closure in preterms—a prospective randomized clinical trial. J. Matern. Fetal Neonatal Med. 33, 1587–1592 (2020).
Yurttutan, S. et al. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J. Matern. Fetal Neonatal Med. 26, 825–7 (2013).
Liebowitz, M. et al. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial. J. Perinatol. 39, 599–607 (2019).
Clyman, R. I. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J. Pediatr. 128, 601–7 (1996).
McPherson, C., Luecke, C. M., Liviskie, C. J., Zeller, B. N. & Vesoulis, Z. A. Acetaminophen serum concentrations in infants treated intravenously for patent ductus arteriosus. J. Pediatr. Pharm. Ther. 24, 134–137 (2019).
Bell, E. F. & Acarregui, M. J. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst. Rev. 12, CD000503 (2014).
Hansson, L., Lind, T., Wiklund, U., Öhlund, I. & Rydberg, A. Fluid restriction negatively affects energy intake and growth in very low birthweight infants with haemodynamically significant patent ductus arteriosus. Acta Paediatr. 108, 1985–1992 (2019).
De Buyst, J., Rakza, T., Pennaforte, T., Johansson, A. B. & Storme, L. Hemodynamic effects of fluid restriction in preterm infants with significant patent ductus arteriosus. J. Pediatr. 161, 404–8 (2012).
The authors declare no competing interests.
Patient consent was not required.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Gover, A., Levy, P.T., Rotschild, A. et al. Oral versus intravenous paracetamol for patent ductus arteriosus closure in preterm infants. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-01944-w
Pediatric Research (2022)