Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants

Journal of Perinatology volume 44, pages 388–395 (2024)Cite this article

Subjects

Abstract

Objective

Assess if unit-level PDA management correlates with neurodevelopmental impairment (NDI) at 18–24 months corrected postnatal age (CPA) in extremely preterm infants.

Study design

Retrospective analysis of infants born at <29 weeks (2014–2017) across two units having distinct PDA strategies. Site 1 utilized an echocardiography-based treatment strategy aiming for accelerated closure (control). Site 2 followed a conservative approach. Primary endpoint: NDI, characterized by cerebral palsy, any Bayley-III composite score <85, sensorineural/mixed hearing loss, or at least unilateral visual impairment.

Results

377 infants were evaluated. PDA treatment rates remained unchanged in Site 1 but eventually reached 0% in Site 2. Comparable rates of any/significant NDI were seen across both sites (any NDI: 38% vs 36%; significant NDI: 13% vs 10% for Site 1 and 2, respectively). After adjustments, NDI rates remained similar.

Conclusion

PDA management strategies in extremely preterm newborns showed no significant impact on neurodevelopment outcomes at 18–24 months CPA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flow Diagram of Patient Inclusion and Exclusion.

Similar content being viewed by others

Data availability

Data for this study cannot be shared publicly as it is bound by confidentiality agreements governed by hospital offices. Aggregate data may be made available from the corresponding author (GA) on reasonable request.

References

  1. de Carvalho Nunes G, Wutthigate P, Simoneau J, Beltempo M, Sant’Anna GM, Altit G. Natural evolution of the patent ductus arteriosus in the extremely premature newborn and respiratory outcomes. J Perinatol. 2022;42:642–8.

    PubMed  Google Scholar 

  2. Sung SI, Chang YS, Kim J, Choi JH, Ahn SY, Park WS. Natural evolution of ductus arteriosus with noninterventional conservative management in extremely preterm infants born at 23-28 weeks of gestation. PLoS One. 2019;14:1–11.

    Google Scholar 

  3. Parkerson S, Philip R, Talati A, Sathanandam S. Management of patent ductus arteriosus in premature infants in 2020. Front Pediatr. 2021;8:590578.

    PubMed  PubMed Central  Google Scholar 

  4. Ruoss JL, Bazacliu C, Giesinger RE, McNamara PJ. Patent ductus arteriosus and cerebral, cardiac, and gut hemodynamics in premature neonates. Semin Fetal Neonatal Med. 2020;25:101120.

    CAS  PubMed  Google Scholar 

  5. Weir FJ, Ohlsson A, Myhr TL, Fong K, Ryan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. Eur J Pediatr. 1999;158:484–7.

    CAS  PubMed  Google Scholar 

  6. Rozé JC, Cambonie G, Le Thuaut A, Debillon T, Ligi I, Gascoin G, et al. Effect of early targeted treatment of ductus arteriosus with ibuprofen on survival without cerebral palsy at 2 years in infants with extreme prematurity: a randomized clinical trial. J Pediatr. 2021;233:33–42.e2.

    PubMed  Google Scholar 

  7. Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, et al. Expectant management or early ibuprofen for patent ductus arteriosus. N. Engl J Med. 2023;388:980–90.

    CAS  PubMed  Google Scholar 

  8. Mitra S, Scrivens A, von Kursell AM, Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev. 2020;12:CD013278.

    PubMed  Google Scholar 

  9. Sung SI, Chang YS, Ahn SY, Jo HS, Yang M, Park WS. Conservative non-intervention approach for hemodynamically significant patent ductus arteriosus in extremely preterm infants. Front Pediatr. 2020;8:605134.

    PubMed  PubMed Central  Google Scholar 

  10. Yanowitz TD, Yao AC, Werner JC, Pettigrew KD, Oh W, Stonestreet BS. Effects of prophylactic low-dose indomethacin on hemodynamics in very low birth weight infants. J Pediatr. 1998;132:28–34.

    CAS  PubMed  Google Scholar 

  11. Stark MJ, Crawford TM, Ziegler NM, Hall A, Andersen CC. Differential effects of ibuprofen and indomethacin on cerebral oxygen kinetics in the very preterm baby. Front Pediatr. 2022;10:979112.

    PubMed  PubMed Central  Google Scholar 

  12. Benitz WE. Patent ductus arteriosus in preterm infants. Pediatrics. 2016;137:e20153730.

    Google Scholar 

  13. Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants. Pediatrics. 2017;139:e20162390.

    PubMed  PubMed Central  Google Scholar 

  14. Hagadorn JI, Brownell EA, Trzaski JM, Johnson KR, Lainwala S, Campbell BT, et al. Trends and variation in management and outcomes of very low-birth-weight infants with patent ductus arteriosus. Pediatr Res. 2016;80:785–92.

    PubMed  Google Scholar 

  15. Lokku A, Mirea L, Lee SK, Shah PS. Trends and outcomes of patent ductus arteriosus treatment in very preterm infants in Canada. Am J Perinatol. 2017;34:441–50.

    PubMed  Google Scholar 

  16. Park J, Yoon SJ, Han J, Song IG, Lim J, Shin JE, et al. Patent ductus arteriosus treatment trends and associated morbidities in neonates. Sci Rep. 2021;11:10689.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hagadorn JI, Bennett MV, Brownell EA, Payton KSE, Benitz WE, Lee HC. Covariation of neonatal intensive care unit-level patent ductus arteriosus management and in-neonatal intensive care unit outcomes following preterm birth. J Pediatr. 2018;203:225–233.e1.

    PubMed  Google Scholar 

  18. Shah PS, Seidlitz W, Chan P, Yeh S, Musrap N, Lee SK. Internal audit of the Canadian neonatal network data collection system. Am J Perinatol. 2017;34:1241–9.

    PubMed  Google Scholar 

  19. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82:527–32.

    CAS  PubMed  Google Scholar 

  20. 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. 1978;92:529–34.

    CAS  PubMed  Google Scholar 

  21. Joseph Volpe, Terrie Inder, Basil Darras, Linda de Vries, Adre du Plessis, Jeffrey Neil, et al. Volpe’s Neurology of the Newborn. 6th ed. Elsevier; 484–99 p. (2017).

  22. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tita ATN, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37:339–54.

    PubMed  PubMed Central  Google Scholar 

  24. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol. 2009;200:372.e1–6.

    PubMed  Google Scholar 

  25. International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123:991–9.

    Google Scholar 

  26. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001;108:e35.

    CAS  PubMed  Google Scholar 

  27. Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK, Smith PB, et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev. 2012;88:S69–74.

    PubMed  PubMed Central  Google Scholar 

  28. Gunel MK, Mutlu A, Tarsuslu T, Livanelioglu A. Relationship among the manual ability classification system (MACS), the gross motor function classification system (GMFCS), and the functional status (WeeFIM) in children with spastic cerebral palsy. Eur J Pediatr. 2009;168:477–85.

    PubMed  Google Scholar 

  29. Busque AA, Jabbour E, Patel S, Couture É, Garfinkle J, Khairy M, et al. Incidence and risk factors for autism spectrum disorder among infants born <29 weeks’ gestation. Paediatr Child Health (Can). 2022;27:346–52.

    Google Scholar 

  30. Sankar MN, Benitz WE. Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment? J Perinatol. 2020;40:1863–70.

    PubMed  Google Scholar 

  31. Dani C, Lista G, Bianchi S, Mosca F, Schena F, Ramenghi L, et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr. 2021;180:807–16.

    CAS  PubMed  Google Scholar 

  32. Mari G, Moise KJ, Deter RL, Kirshon B, Huhta JC, Carpenter RJ, et al. Doppler assessment of the pulsatility index of the middle cerebral artery during constriction of the fetal ductus arteriosus after indomethacin therapy. Am J Obstet Gynecol. 1989;161:1528–31.

    CAS  PubMed  Google Scholar 

  33. Chen X, Han D, Wang X, Huang X, Huang Z, Liu Y, et al. Vascular and pulmonary effects of ibuprofen on neonatal lung development. Respir Res. 2023;24:39.

    PubMed  PubMed Central  Google Scholar 

  34. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2015;2015:1–143.

    Google Scholar 

  35. Jansen EJS, Hundscheid T, Onland W, Kooi EMW, Andriessen P, de Boode WP. Factors associated with benefit of treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Front Pediatr. 2021;9:626262.

    PubMed  PubMed Central  Google Scholar 

  36. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. J Pediatrics. 2007;150:229–234.e1.

    CAS  Google Scholar 

  37. Barcroft M, McKee C, Berman DP, Taylor RA, Rivera BK, Smith CV, et al. Percutaneous closure of patent ductus arteriosus. Clin Perinatol. 2022;49:149–66.

    PubMed  PubMed Central  Google Scholar 

  38. Kaga M, Sanjo M, Sato T, Miura Y, Ono T. Safety of conservative approach for persistent patent ductus arteriosus in preterm infants: Neurodevelopmental outcomes at 5 years of age. Tohoku J Exp Med. 2019;249:155–61.

    PubMed  Google Scholar 

  39. Collins RT, Lyle RE, Rettiganti M, Gossett JM, Robbins JM, Casey PH. Long-term neurodevelopment of low-birthweight, preterm infants with patent ductus arteriosus. J Pediatr. 2018;203:170–6.

    PubMed  Google Scholar 

  40. Aldecoa-Bilbao V, García-Catalán MJ, Gaixa M, Clotet Caba J, Teodoro S, Figaró Voltà C. Neurodevelopmental impairment at two years in premature infants with prolonged patency of ductus arteriosus after a conservative approach. Am J Perinatol. 2021;38:449–55.

    PubMed  Google Scholar 

  41. Oncel MY, Eras Z, Uras N, Canpolat FE, Erdeve O, Oguz SS. Neurodevelopmental outcomes of preterm infants treated with oral paracetamol versus ibuprofen for patent ductus arteriosus. Am J Perinatol. 2017;34:1185–9.

    PubMed  Google Scholar 

  42. Weisz DE, Mirea L, Rosenberg E, Jang M, Ly L, Church PT, et al. Association of patent ductus arteriosus ligation with death or neurodevelopmental impairment among extremely preterm infants. JAMA Pediatr. 2017;171:443–9.

    PubMed  PubMed Central  Google Scholar 

  43. Janz-Robinson EM, Badawi N, Walker K, Bajuk B, Abdel-Latif ME, Bowen J, et al. Neurodevelopmental outcomes of premature infants treated for patent ductus arteriosus: a population-based Cohort Study. J Pediatrics. 2015;167:1025–1032.e3.

    Google Scholar 

  44. Gudmundsdottir A, Broström L, Skiöld B, Källén K, Serenius F, Norman M, et al. The type and timing of patent ductus arteriosus treatment was associated with neurodevelopment when extremely preterm infants reached 6.5 years. Acta Paediatr, Int J Paediatr. 2021;110:510–20.

    Google Scholar 

  45. Wickremasinghe AC, Rogers EE, Piecuch RE, Johnson BC, Golden S, Moon-Grady AJ, et al. Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus. J Pediatr. 2012;161:1065–72.

    PubMed  PubMed Central  Google Scholar 

  46. de Waal K, Phad N, Stubbs M, Chen Y, Kluckow M. A randomized placebo-controlled pilot trial of early targeted nonsteroidal anti-inflammatory drugs in preterm infants with a patent ductus arteriosus. J Pediatr. 2021;228:82–86.e2.

    PubMed  Google Scholar 

  47. Schindler T, Smyth J, Bolisetty S, Michalowski J, Mallitt KA, 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.

    CAS  PubMed  Google Scholar 

  48. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, et al. PDA-TOLERATE Trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. J Pediatr. 2019;205:41–48.e6.

    PubMed  Google Scholar 

  49. EL-Khuffash A, Bussmann N, Breatnach CR, Smith A, Tully E, Griffin J, et al. A pilot randomized controlled trial of early targeted patent ductus arteriosus treatment using a risk based severity score (The PDA RCT). J Pediatr. 2021;229:127–33.

    CAS  PubMed  Google Scholar 

  50. Giesinger RE, Hobson AA, Bischoff AR, Klein JM, McNamara PJ. Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in “22-23” week and “24-26” infants. Semin Perinatol. 2023;47:151721.

    CAS  PubMed  Google Scholar 

  51. Kristman V, Manno M, Côté P. Loss to follow-up in cohort studies: How much is too much? Eur J Epidemiol. 2004;19:751–60.

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Canadian Neonatal Network and the Canadian Neonatal Follow Up Network who provided the local database of the 2 centers with the standardized definitions.

Funding

This project was supported by the Neonatology divisions of Centre Hospitalier Universitaire Sainte-Justine and McGill University Health Centre. The NeoCardioLab and its platforms were funded by the Department of Pediatrics of McGill University, the Just for Kids Foundation, the Foundation of Stars, as well as the Grand Defi Pierre Lavoie.

Author information

Author notes

  1. These authors jointly supervised this work: Sophie Tremblay, Gabriel Altit.

Authors and Affiliations

  1. Division of Neonatology, Department of Paediatrics, Sainte-Justine University Health Center, Montréal, QC, Canada

    Soledad Belén Cervera, Anie Lapointe, Sophie Tremblay & Gabriel Altit

  2. Department of Public Health Sciences, Queen’s University, Kingston, ON, Canada

    Sahar Saeed

  3. Neonatal Follow-Up, Department of Paediatrics, Université de Montréal, Montreal, QC, Canada

    Thuy Mai Luu

  4. Neonatal Follow-Up, Department of Pediatrics, McGill University, Montreal, QC, Canada

    Andrea Gorgos

  5. Division of Neonatology, Department of Pediatrics, McGill University, Montreal, QC, Canada

    Marc Beltempo & Martine Claveau

  6. Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada

    Olga Basso

Authors
  1. Soledad Belén Cervera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sahar Saeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thuy Mai Luu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Gorgos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc Beltempo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martine Claveau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Olga Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anie Lapointe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sophie Tremblay
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gabriel Altit
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TML, MB, AG, SS, OB, MC interpreted the results and critically reviewed the manuscript for important intellectual content. ST, AL conceptualized and designed the study, interpreted the results, supervised the student work and reviewed and revised all manuscript drafts for important intellectual content. GA conceptualized and designed the study, conducted the analyses interpreted the results, and reviewed and revised all manuscript drafts for important intellectual content. SBC conceptualized the study, conducted the analyses, interpreted the results and wrote the paper. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Gabriel Altit.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cervera, S.B., Saeed, S., Luu, T.M. et al. Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants. J Perinatol 44, 388–395 (2024). https://doi.org/10.1038/s41372-024-01877-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-024-01877-8

Search

Advanced search

Quick links