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.

  • Clinical Research Article
  • Published:

Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension

Pediatric Research volume 94, pages 547–554 (2023)Cite this article

Abstract

Background

The aim of the study was to determine whether prolonged exposure to a moderate/large patent ductus arteriosus left-to-right shunt (PDA) increases the risk of late (beyond 36 weeks) pulmonary hypertension (BPD-PH) and pulmonary vascular disease (BPD-PVD) during the neonatal hospitalization in preterm infants (<28 weeks’ gestation) with bronchopulmonary dysplasia (BPD).

Methods

All infants requiring respiratory support ≥36 weeks had systematic echocardiographic evaluations for BPD-PH at planned intervals. Infants were classified as having either flow-associated BPD-PH (BPD-flow-PH) or BPD-PVD.

Results

256 infants survived ≥36 weeks: 105 had NO BPD (were off respiratory support by 36 weeks); 151 had BPD. 22/151 had BPD-PH (12/22 had BPD-flow-PH from a PDA that persisted beyond 36 weeks; 10/22 had BPD-PVD). Moderate/large PDA shunts that persisted beyond 36 weeks were significantly associated with an increased incidence of BPD-PH due to BPD-flow-PH. We found no association between the duration of PDA exposure and the incidence of BPD-PVD.

Conclusions

Moderate/large PDA shunts increase the risk of flow-associated BPD-PH when present beyond 36 weeks. Although term infants with PDA-congenital heart disease can develop pulmonary vascular remodeling and PVD after months of PDA exposure, we found no echocardiographic evidence in preterm infants that prolonged PDA exposure increases the incidence of BPD-PVD during the neonatal hospitalization.

Impact

  • In our study, preterm infants (<28 weeks’ gestation) with bronchopulmonary dysplasia (BPD) had a 15% incidence of pulmonary hypertension (PH) beyond 36 weeks’ postmenstrual age as a comorbidity.

  • Moderate/large patent ductus arteriosus (PDA) shunts increased the risk of flow-associated PH when present beyond 36 weeks.

  • Although months of prolonged PDA exposure can cause pulmonary vascular remodeling and pulmonary vascular disease (PVD) in term infants with PDA-congenital heart disease, we found no echocardiographic evidence for an association between the duration of PDA exposure and the incidence of late PVD during the neonatal hospitalization in preterm infants with BPD.

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 distribution.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Ehrenkranz, R. A. et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116, 1353–1360 (2005).

    Article  PubMed  Google Scholar 

  2. Walsh, M. C. et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 114, 1305–1311 (2004).

    Article  PubMed  Google Scholar 

  3. Shennan, A. T., Dunn, M. S., Ohlsson, A., Lennox, K. & Hoskins, E. M. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 82, 527–532 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Jensen, E. A. et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach. Am. J. Respir. Crit. Care Med. 200, 751–759 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Khemani, E. et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 120, 1260–1269 (2007).

    Article  PubMed  Google Scholar 

  6. Bhat, R., Salas, A. A., Foster, C., Carlo, W. A. & Ambalavanan, N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 129, e682–e689 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bland, R. D. et al. Chronic lung injury in preterm lambs: abnormalities of the pulmonary circulation and lung fluid balance. Pediatr. Res. 48, 64–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Hocq, C. et al. Early diagnosis and targeted approaches to pulmonary vascular disease in bronchopulmonary dysplasia. Pediatr. Res. 91, 804–815 (2022).

    Article  PubMed  Google Scholar 

  9. Pierro, M. et al. Association of the dysfunctional placentation endotype of prematurity with bronchopulmonary dysplasia: a systematic review, meta-analysis and meta-regression. Thorax 77, 268–275 (2022).

    Article  PubMed  Google Scholar 

  10. Parker, T. A. & Abman, S. H. The pulmonary circulation in bronchopulmonary dysplasia. Semin. Neonatol. 8, 51–61 (2003).

    Article  PubMed  Google Scholar 

  11. Nagiub, M., Kanaan, U., Simon, D. & Guglani, L. Risk factors for development of pulmonary hypertension in infants with bronchopulmonary dysplasia: systematic review and meta-analysis. Paediatr. Respir. Rev. 23, 27–32 (2017).

    PubMed  Google Scholar 

  12. Chen, Y. et al. Risk factors and outcomes of pulmonary hypertension in infants with bronchopulmonary dysplasia: a meta-analysis. Front. Pediatr. 9, 695610 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arjaans, S. et al. Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: a systematic review and meta-analysis. Paediatr. Perinat. Epidemiol. 32, 258–267 (2018).

    Article  PubMed  Google Scholar 

  14. Clyman, R. I., Mauray, F., Heymann, M. A. & Roman, C. Cardiovascular effects of a patent ductus arteriosus in preterm lambs with respiratory distress. J. Pediatr. 111, 579–587 (1987).

    Article  CAS  PubMed  Google Scholar 

  15. Alpan, G., Scheerer, R., Bland, R. D. & Clyman, R. Patent ductus arteriosus increases lung fluid filtration in preterm lambs. Pediatr. Res. 30, 616–621 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Diller, G. P. & Gatzoulis, M. A. Pulmonary vascular disease in adults with congenital heart disease. Circulation 115, 1039–1050 (2007).

    Article  PubMed  Google Scholar 

  17. D'Alto, M. & Mahadevan, V. S. Pulmonary arterial hypertension associated with congenital heart disease. Eur. Respir. Rev. 21, 328–337 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liebowitz, M. & Clyman, R. I. Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: effects on neonatal outcomes. J. Pediatr. 187, 119–126 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jhaveri, N., Moon-Grady, A. & Clyman, R. I. Early surgical ligation versus a conservative approach for management of patent ductus arteriosus that fails to close after indomethacin treatment. J. Pediatr. 157, 381–387 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  20. El Hajjar, M., Vaksmann, G., Rakza, T., Kongolo, G. & Storme, L. Severity of the ductal shunt: a comparison of different markers. Arch. Dis. Child. Fetal Neonatal Ed. 90, F419–F422 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koch, J. et al. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 117, 1113–1121 (2006).

    Article  PubMed  Google Scholar 

  22. Clyman, R. I. 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. 205, 41–48 (2019).

    Article  PubMed  Google Scholar 

  23. Abman, S. H. et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation 132, 2037–2099 (2015).

    Article  PubMed  Google Scholar 

  24. Krishnan, U. et al. Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia. J. Pediatr. 188, 24.e1–34.e1 (2017).

    Article  Google Scholar 

  25. Berkelhamer, S. K., Mestan, K. K. & Steinhorn, R. An update on the diagnosis and management of bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension. Semin. Perinatol. 42, 432–443 (2018).

    Article  PubMed  Google Scholar 

  26. Hansmann, G. et al. Pulmonary hypertension in bronchopulmonary dysplasia. Pediatr. Res. 89, 446–455 (2021).

    Article  PubMed  Google Scholar 

  27. Nawaytou, H. et al. Clinical utility of echocardiography in former preterm infants with bronchopulmonary dysplasia. J. Am. Soc. Echocardiogr. 33, 378.e1–388.e1 (2020).

    Article  Google Scholar 

  28. Fenton, T. R. & Kim, J. H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 13, 59 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight <1500 grams. J. Pediatr. 92, 529–534 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. Bell, M. J. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 187, 1–7 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mourani, P. M., Sontag, M. K., Younoszai, A., Ivy, D. D. & Abman, S. H. Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics 121, 317–325 (2008).

    Article  PubMed  Google Scholar 

  32. McCrary, A. W. et al. Agreement of an echocardiogram-based diagnosis of pulmonary hypertension in infants at risk for bronchopulmonary dysplasia among masked reviewers. J. Perinatol. 39, 248–255 (2019).

    Article  PubMed  Google Scholar 

  33. Ge, Z. M. et al. Reliability and accuracy of measurement of transductal gradient by Doppler ultrasound. Int. J. Cardiol. 40, 35–43 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Groh, G. K. et al. Doppler echocardiography inaccurately estimates right ventricular pressure in children with elevated right heart pressure. J. Am. Soc. Echocardiogr. 27, 163–171 (2014).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Mark Cocalis, Dr. Michael Brook, Dr. Anita Moon-Grady, Dr. Shabnam Peyvandi, Dr. Nicole Cresalia, Dr. Kavitha Pundi, Dr. Shafkat Anwar, and Dr. Emilio Quezada for their expert help in reading and interpreting the echocardiograms and to the neonatal faculty, fellows, nurses, respiratory therapists, and dieticians for their excellent care and their commitment to the nursery’s quality improvement projects and its consensus-driven protocols.

Funding

This work was supported by a grant from U.S. Public Health Service NHLBI (HL109199) and by gifts from the Clyman Family Foundation.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

    Hythem Nawaytou & Ronald I. Clyman

  2. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    Nancy K. Hills

  3. Department of Neurology, University of California San Francisco, San Francisco, CA, USA

    Nancy K. Hills

  4. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

    Ronald I. Clyman

Authors
  1. Hythem Nawaytou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy K. Hills
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald I. Clyman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The following authors have made the following contributions: (1) H.N., N.K.H., and R.I.C. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) H.N., N.K.H., and R.I.C. have drafted the article or revised it critically for important intellectual content; and (3) H.N., N.K.H., and R.I.C. have given final approval of the version to be published.

Corresponding author

Correspondence to Ronald I. Clyman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The requirement for individual Research HIPAA Authorization was waived by the Institutional Review Board of the University of California San Francisco.

Additional information

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

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

Nawaytou, H., Hills, N.K. & Clyman, R.I. Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension. Pediatr Res 94, 547–554 (2023). https://doi.org/10.1038/s41390-023-02522-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02522-4

Search

Advanced search

Quick links