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:

Neonatal outcomes of preterm infants with pulmonary hypertension: clustering based on prenatal risk factors

Pediatric Research (2024)Cite this article

Abstract

Background

To investigate association of prenatal risk factors and neonatal outcomes of preterm infants with pulmonary hypertension (PH).

Methods

A prospective cohort study of very-low-birth-weight infants born at 22–29 weeks’ gestation who received PH-specific treatment during hospitalization. Infants were classified using a two-step cluster analysis based on gestational age (GA), small-for-gestational-age (SGA), exposure to antenatal corticosteroids (ACS), histologic chorioamnionitis (HCA), and oligohydramnios.

Results

Among 910 infants, six clusters were identified: cluster A (HCA, n = 240), cluster B (oligohydramnios, n = 79), cluster C (SGA, n = 74), cluster D (no-ACS, n = 109), cluster E (no dominant parameter, n = 287), and cluster F (HCA and oligohydroamnios, n = 121). Cluster A was used as a reference group for comparisons among clusters. Compared to cluster A, cluster C (aHR: 1.63 [95% CI: 1.17–2.26]) had higher risk of overall in-hospital mortality. Clusters B (aHR: 1.52 [95% CI: 1.09–2.11]), D (aHR: 1.71 [95% CI: 1.28–2.30]), and F (aHR: 1.51 [95% CI: 1.12–2.03]) had higher risks of receiving PH-specific treatment within the first week of birth compared to cluster A.

Conclusion

These findings may provide a better understanding of prenatal risk factors contributing to the development of PH.

Impact

  • Pulmonary hypertension (PH), presenting as hypoxic respiratory failure, has complex etiologies in preterm infants.

  • Although multifactorial risks for the development of PH in preterm infants are known, few studies have classified infants with similar etiologies for PH.

  • Each cluster has distinct patterns of prenatal condition and neonatal outcome.

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 chart showing the selection of study population.
Fig. 2

Similar content being viewed by others

Data availability

The Korean Neonatal Network (KNN) Publication Ethics Policy adheres to the following research data management and access guidelines. All information about patients and participating NICUs are confidential. They might be used by individuals for approved research purposes. If an individual or institution that is not affiliated with KNN wants to use the data, it must make an official request to the KNN publication-Ethics Committee and obtain approval from the network.

References

  1. Mirza, H., Mandell, E. W., Kinsella, J. P., McNamara, P. J. & Abman, S. H. Pulmonary vascular phenotypes of prematurity: the path to precision medicine. J. Pediatr. 259, 113444 (2023).

    Article  PubMed  Google Scholar 

  2. Arjaans, S. et al. Clinical significance of early pulmonary hypertension in preterm infants. J. Pediatr. 251, 74–81.e3 (2022).

    Article  PubMed  Google Scholar 

  3. Kim, H. H. et al. Early pulmonary hypertension is a risk factor for bronchopulmonary dysplasia-associated late pulmonary hypertension in extremely preterm infants. Sci. Rep. 11, 11206 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mirza, H. et al. Natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and risk for death or bronchopulmonary dysplasia. J. Pediatr. 198, 187–193.e181 (2018).

    Article  PubMed  Google Scholar 

  5. Nakanishi, H., Suenaga, H., Uchiyama, A. & Kusuda, S. Persistent pulmonary hypertension of the newborn in extremely preterm infants: a Japanese cohort study. Arch. Dis. Child Fetal Neonatal Ed. 103, F554–F561 (2018).

    Article  PubMed  Google Scholar 

  6. Al-Ghanem, G. et al. Bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis. J. Perinatol. 37, 414–419 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Ruoss, J. L., Rios, D. R. & Levy, P. T. Updates on management for acute and chronic phenotypes of neonatal pulmonary hypertension. Clin. Perinatol. 47, 593–615 (2020).

    Article  PubMed  Google Scholar 

  9. Goss, K. Long-term pulmonary vascular consequences of perinatal insults. J. Physiol. 597, 1175–1184 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Seth, S. A., Soraisham, A. S. & Harabor, A. Risk factors and outcomes of early pulmonary hypertension in preterm infants. J. Matern. Fetal Neonatal Med. 31, 3147–3152 (2018).

    Article  PubMed  Google Scholar 

  11. Check, J. et al. Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia. J. Perinatol. 33, 553–557 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim, D.-H. et al. Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology 101, 40–46 (2011).

    Article  PubMed  Google Scholar 

  13. Taglauer, E., Abman, S. H. & Keller, R. L. Recent advances in antenatal factors predisposing to bronchopulmonary dysplasia. Semin. Perinatol. 42, 413–424 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Abman, S. H. Pulmonary hypertension: the hidden danger for newborns. Neonatology 118, 211–217 (2021).

    Article  PubMed  Google Scholar 

  15. Polglase, G. R. et al. Intrauterine inflammation causes pulmonary hypertension and cardiovascular sequelae in preterm lambs. J. Appl. Physiol. 108, 1757–1765 (2010).

    Article  PubMed  Google Scholar 

  16. Williams, O., Hutchings, G., Hubinont, C., Debauche, C. & Greenough, A. Pulmonary effects of prolonged oligohydramnios following mid-trimester rupture of the membranes–antenatal and postnatal management. Neonatology 101, 83–90 (2012).

    Article  PubMed  Google Scholar 

  17. Mohseni-Bod, H. & Bohn, D. Pulmonary hypertension in congenital diaphragmatic hernia. Semin. Pediatr. Surg. 16, 126–133 (2007).

    Article  PubMed  Google Scholar 

  18. Barros, F. C. et al. The distribution of clinical phenotypes of preterm birth syndrome: implications for prevention. JAMA Pediatr. 169, 220–229 (2015).

    Article  PubMed  Google Scholar 

  19. Maron, B. A. & Abman, S. H. Translational advances in the field of pulmonary hypertension. Focusing on developmental origins and disease inception for the prevention of pulmonary hypertension. Am. J. Respir. Crit. Care Med. 195, 292–301 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barrington, K. J., Finer, N. & Pennaforte, T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst. Rev. 1, Cd000509 (2017).

    PubMed  Google Scholar 

  21. Villar, J. et al. Association between preterm-birth phenotypes and differential morbidity, growth, and neurodevelopment at age 2 years: results from the INTERBIO-21st newborn study. JAMA Pediatr. 175, 483–493 (2021).

    Article  PubMed  Google Scholar 

  22. Chang, Y. S., Park, H.-Y. & Park, W. S. The Korean neonatal network: an overview. J. Korean Med. Sci. 30, S3–S11 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Singh, Y. & Lakshminrusimha, S. Pathophysiology and management of persistent pulmonary hypertension of the newborn. Clin. Perinatol. 48, 595–618 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bacher, J, Wenzig, K & Vogler, M. SPSS TwoStep Cluster—a First Evaluation. (Department of Sociology, Social Science Institute, Friedrich-Alexander-University: Erlangen-Nuremberg, Germany, 2004) 1–30.

    Google Scholar 

  25. Kent, P., Jensen, R. K. & Kongsted, A. A comparison of three clustering methods for finding subgroups in MRI, SMS or clinical data: SPSS TwoStep cluster analysis, latent gold and snob. BMC Med. Res. Methodol. 14, 113 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rohan, J. M. et al. Identification of self-management patterns in pediatric type 1 diabetes using cluster analysis. Pediatr. Diabetes 12, 611–618 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Huang, R. C. et al. Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents. Hepatology 58, 1306–1314 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Kaufman L. & Rousseeuw P. J. Finding Groups in Data: An Introduction to Cluster Analysis (John Wiley & Sons, 2005).

  29. Finken, M. J. J. et al. Children born small for gestational age: differential diagnosis, molecular genetic evaluation, and implications. Endocr. Rev. 39, 851–894 (2018).

    Article  PubMed  Google Scholar 

  30. Goldenberg, R. L., Hauth, J. C. & Andrews, W. W. Intrauterine infection and preterm delivery. N. Engl. J. Med. 342, 1500–1507 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Mourani, P. M. et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 191, 87–95 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mehler, K. et al. An echocardiographic screening program helps to identify pulmonary hypertension in extremely low birthweight infants with and without bronchopulmonary dysplasia: a single-center experience. Neonatology 113, 81–88 (2018).

    Article  PubMed  Google Scholar 

  33. Sallmon, H. et al. Extremely premature infants born at 23–25 weeks gestation are at substantial risk for pulmonary hypertension. J. Perinatol. 42, 781–787 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kramer, B. W. et al. Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr. Res. 58, 607–612 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Miller, J. D., Benjamin, J. T., Kelly, D. R., Frank, D. B. & Prince, L. S. Chorioamnionitis stimulates angiogenesis in saccular stage fetal lungs via CC chemokines. Am. J. Physiol. Lung Cell Mol. Physiol. 298, L637–L645 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yum, S. K. et al. Impact of histologic chorioamnionitis on pulmonary hypertension and respiratory outcomes in preterm infants. Pulm. Circ. 8, 2045894018760166 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kim, S. Y. et al. Neonatal morbidities associated with histologic chorioamnionitis defined based on the site and extent of inflammation in very low birth weight infants. J. Korean Med. Sci. 30, 1476–1482 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Villamor-Martinez, E. et al. Association of chorioamnionitis with bronchopulmonary dysplasia among preterm infants: a systematic review, meta-analysis, and metaregression. JAMA Netw. Open 2, e1914611–e1914611 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wu, C.-S., Chen, C.-M. & Chou, H.-C. Pulmonary hypoplasia induced by oligohydramnios: findings from animal models and a population-based study. Pediatr. Neonatol. 58, 3–7 (2017).

    Article  PubMed  Google Scholar 

  40. Kim, Y. J., Shin, S. H., Park, H. W., Kim, E. K. & Kim, H. S. Risk factors of early pulmonary hypertension and its clinical outcomes in preterm infants: a systematic review and meta-analysis. Sci. Rep. 12, 14186 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Daayana, S., Baker, P. & Crocker, I. An image analysis technique for the investigation of variations in placental morphology in pregnancies complicated by preeclampsia with and without intrauterine growth restriction. J. Soc. Gynecol. Investig. 11, 545–552 (2004).

    Article  PubMed  Google Scholar 

  42. Gumina, D. L., Black, C. P., Balasubramaniam, V., Winn, V. D. & Baker, C. D. Umbilical cord blood circulating progenitor cells and endothelial colony-forming cells are decreased in preeclampsia. Reprod. Sci. 24, 1088–1096 (2017).

    Article  PubMed  Google Scholar 

  43. Di Fiore, J. M. et al. Patterns of oxygenation, mortality, and growth status in the surfactant positive pressure and oxygen trial cohort. J. Pediatr. 186, 49–56.e41 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Walsh, M. C. et al. Association of oxygen target and growth status with increased mortality in small for gestational age infants: further analysis of the surfactant, positive pressure and pulse oximetry randomized trial. JAMA Pediatr. 170, 292–294 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Boghossian, N. S., Geraci, M., Edwards, E. M. & Horbar, J. D. Morbidity and mortality in small for gestational age infants at 22 to 29 weeks’ gestation. Pediatrics 141, e20172533 (2018).

    Article  PubMed  Google Scholar 

  46. Breinig, S. et al. Pulmonary hypertension among preterm infants born at 22 through 32 weeks gestation in France: prevalence, survival, morbidity and management in the EPIPAGE-2 cohort study. Early Hum. Dev. 184, 105837 (2023).

    Article  PubMed  Google Scholar 

  47. Ryu, Young, H., Oh, S., Sohn, J. & Lee, J. The associations between antenatal corticosteroids and in-hospital outcomes of preterm singleton appropriate for gestational age neonates according to the presence of maternal histologic chorioamnionitis. Neonatology 116, 369–375 (2019).

    Article  CAS  PubMed  Google Scholar 

  48. Bird, A. D., Choo, Y. L., Hooper, S. B., McDougall, A. R. & Cole, T. J. Mesenchymal glucocorticoid receptor regulates the development of multiple cell layers of the mouse lung. Am. J. Respir. Cell Mol. Biol. 50, 419–428 (2014).

    Article  PubMed  Google Scholar 

  49. Bridges, J. P. et al. Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function. Am. J. Physiol. Lung Cell. Mol. Physiol. 319, L239–l255 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Konduri, G. G., Bakhutashvili, I., Eis, A. & Afolayan, A. Antenatal betamethasone improves postnatal transition in late preterm lambs with persistent pulmonary hypertension of the newborn. Pediatr. Res. 73, 621–629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. El-Saie, A. et al. Bronchopulmonary dysplasia—associated pulmonary hypertension: an updated review. Semin. Perinatol. 47, 151817 (2023).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by a research grant (2022-ER0603-00#) funded by Korea National Institute of Health.

Funding

This research was supported by Soonchunhyang University Research Fund (grant number 2022-1214) to cover publication costs. The funder had no role in (1) the design, (2) the collection, analysis, and interpretation of data, (3) the writing of the report, or (4) the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

    Seong Phil Bae & Hanbyul Lee

  2. Department of Pediatrics, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea

    Seong Phil Bae, Sung Shin Kim & Hanbyul Lee

  3. Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea

    Sung Shin Kim

  4. Department of Pediatrics, The Catholic University of Korea Eunpyeong St. Mary’s Hospital, Seoul, Republic of Korea

    Jungha Yun

  5. Department of Pediatrics, Inha University Hospital, Incheon, Republic of Korea

    Won-Ho Hahn

  6. Department of Biostatistics, Academic Research Office, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

    Suyeon Park

  7. Department of Applied Statistics, Chung-Ang University, Seoul, Republic of Korea

    Suyeon Park

Authors
  1. Seong Phil Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sung Shin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jungha Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanbyul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Won-Ho Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suyeon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.P.B. and S.S.K. conceptualized and designed the research. S.P.B. and S.P. collected and analyzed the data. S.P.B. and J.Y. wrote the manuscript. H.L. assisted with study design and reviewed the manuscript. S.S.K. and W.H.H. reviewed and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sung Shin Kim.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent to participate

Participation of infants in the registration of data in the KNN was approved by the Institutional Review Board (IRB) of each participating center. Written informed consent was obtained from parents of each participant in the study.

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

Bae, S.P., Kim, S.S., Yun, J. et al. Neonatal outcomes of preterm infants with pulmonary hypertension: clustering based on prenatal risk factors. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03232-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-024-03232-1

Search

Advanced search

Quick links