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:

Prophylactic Indomethacin in extremely preterm infants: association with death or BPD and observed early serum creatinine levels

Journal of Perinatology volume 41, pages 749–755 (2021)Cite this article

Subjects

Abstract

Objectives

To identify the relationship between prophylactic indomethacin (PI) administration and (1) mortality and bronchopulmonary dysplasia (BPD) at 36-week postmenstrual age (PMA) (primary outcome), and (2) to evaluate for PI-associated acute kidney injury.

Study design

Retrospective cohort investigation of 22–28 weeks gestation infants (N = 1167) who were admitted to Nationwide Children’s Hospital on postnatal days 0–1 between May 2009 and September 2017 and survived ≥24-h postnatal. The associations of PI treatment with mortality or BPD, and other secondary outcomes, were evaluated via multivariable robust-error-variance Poisson regression.

Results

The adjusted risks of death or BPD (1.02, 95% CI: 0.83, 1.25), BPD (0.97, 95% CI: 0.77, 1.21), and death 1.33 (95% CI: 0.84, 2.10) by 36-week PMA were unchanged following PI treatment after multivariable adjustment. No changes in mean creatinine levels were detected in exposed versus unexposed infants to suggest PI-induced AKI.

Conclusion

Prophylactic indomethacin treatment was unrelated to mortality or BPD outcomes.

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: Medium serum creatinine levels measured in the first postnatal week.

Similar content being viewed by others

References

  1. 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.

  2. Slaughter JL, Cua CL, Notestine JL, Rivera BK, Marzec L, Hade EM, et al. Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation. BMC Pediatrics. 2019;19:333.

    Article  Google Scholar 

  3. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;7:CD000174.

  4. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001;344:1966–1972.

    Article  CAS  Google Scholar 

  5. Slaughter JL, Reagan PB, Newman TB, Klebanoff MA. Comparative effectiveness of nonsteroidal anti-inflammatory drug treatment vs no treatment for patent ductus arteriosus in preterm infants. JAMA Pediatr. 2017;171:e164354.

    Article  Google Scholar 

  6. Jensen EA, Dysart KC, Gantz MG, Carper B, Higgins RD, Keszler M, et al. Association between use of prophylactic indomethacin and the risk for bronchopulmonary dysplasia in extremely preterm infants. J Pediatr. 2017;186:34–40.e32.

    Article  CAS  Google Scholar 

  7. Fowlie PW. Prophylactic indomethacin: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 1996;74:F81–F87.

    Article  CAS  Google Scholar 

  8. Jensen EA, Foglia EE, Schmidt B. Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies. Semin Perinatol. 2018;42:228–234.

    Article  Google Scholar 

  9. Liebowitz M, Clyman RI. Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: effects on neonatal outcomes. J Pediatr. 2017;187:119–126.e111.

    Article  CAS  Google Scholar 

  10. Nelin TD, Pena E, Giacomazzi T, Lee S, Logan JW, Moallem M, et al. Outcomes following indomethacin prophylaxis in extremely preterm infants in an all-referral NICU. J Perinatol. 2017;37:932–937.

    Article  CAS  Google Scholar 

  11. Papile LA, 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;92:529–534.

    Article  CAS  Google Scholar 

  12. Couser RJ, Ferrara TB, Wright GB, Cabalka AK, Schilling CG, Hoekstra RE, et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr. 1996;128:631–637.

    Article  CAS  Google Scholar 

  13. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994;93:543–550.

    Article  CAS  PubMed  Google Scholar 

  14. Akima S, Kent A, Reynolds G, Gallagher M, Falk M. Indomethacin and renal impairment in neonates. Pediatr Nephrol. 2004;19:490–493.

    Article  Google Scholar 

  15. Cifuentes RF, Olley PM, Balfe JW, Radde IC, Soldin SJ. Indomethacin and renal function in premature infants with persistent patent ductus arteriosus. J Pediatr. 1979;95:583–587.

    Article  CAS  Google Scholar 

  16. Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr. 1983;102:895–906.

    Article  CAS  Google Scholar 

  17. Shaffer CL, Gal P, Ransom JL, Carlos RQ, Smith MS, Davey AM, et al. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Crit Care Med. 2002;30:343–348.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87:163–168.

    Article  CAS  Google Scholar 

  20. Pishevar N, Fathi O, Backes CH, Shepherd EG, Nelin LD. Predicting survival in infants born at <27 weeks gestation admitted to an all referral neonatal intensive care unit: a pilot study. J Perinatol. 2020;40:750–757.

    Article  CAS  Google Scholar 

  21. Altit G, Basso O, Grandi SM, Yang S. Letter to the editor. J Perinatol. 2018;38:767.

    Article  Google Scholar 

  22. Rolnitsky A, Lee SK, Piedbouf B, Harrison A, Shah PS, Canadian Neonatal N. Prophylactic interventions in neonatology: how do they fare in real life? Am J Perinatol. 2015;32:1098–1104.

    Article  Google Scholar 

  23. Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani HM, Nwaesei C, et al. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: Further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). The. J Pediatr. 2006;148:730–734.e731.

    Article  CAS  Google Scholar 

  24. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr. 1996;128:601–607.

    Article  CAS  Google Scholar 

  25. Nada A, Bonachea EM, Askenazi D. Acute kidney injury in the fetus and neonate. Semin Fetal Neonatal Med. 2017;22:90–97.

    Article  Google Scholar 

  26. Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, et al. Neonatal acute kidney injury. Pediatrics 2015;136:e463–e473.

    Article  Google Scholar 

  27. Hanna MH, Askenazi DJ, Selewski DT. Drug induced acute kidney injury in neonates. Curr Opin Pediatr. 2016;28:180–187.

    Article  CAS  Google Scholar 

  28. Bateman DA, Thomas W, Parravicini E, Polesana E, Locatelli C, Lorenz JM. Serum creatinine concentration in very-low-birth-weight infants from birth to 34-36 wk postmenstrual age. Pediatr Res. 2015;77:696–702.

    Article  CAS  Google Scholar 

  29. Mirza H, Oh W, Laptook A, Vohr B, Tucker R, Stonestreet BS. Indomethacin prophylaxis to prevent intraventricular hemorrhage: association between incidence and timing of drug administration. J Pediatr. 2013;163:706–710.e701.

    Article  CAS  Google Scholar 

  30. Mirza H, Laptook AR, Oh W, Vohr BR, Stoll BJ, Kandefer S, et al. Effects of indomethacin prophylaxis timing on IVH and PDA in extremely low birth weight (ELBW) infants. Arch Dis Child Fetal Neonatal Ed. 2016;101:F418–F422.

    Article  Google Scholar 

  31. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2007;167:492–499.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health [R01HL145032] and Nationwide Children’s Hospital.

Author information

Authors and Affiliations

  1. Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    Hibo H. Abdi, Carl H. Backes, Molly K. Ball, Mark A. Klebanoff, Sudarshan R. Jadcherla & Jonathan L. Slaughter

  2. Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA

    Carl H. Backes, Molly K. Ball, Mark A. Klebanoff, Sudarshan R. Jadcherla, Tahagod H. Mohamed & Jonathan L. Slaughter

  3. Division of Neonatology, Nationwide Children’s Hospital, Columbus, OH, USA

    Carl H. Backes, Molly K. Ball, Sudarshan R. Jadcherla & Jonathan L. Slaughter

  4. The Heart Center, Nationwide Children’s Hospital, Columbus, OH, USA

    Carl H. Backes

  5. Avera Research Institute Center for Pediatric and Community Research, Avera McKenna Hospital and University Healtch Center, Sioux Falls, SD, USA

    Maria M. Talavera-Barber

  6. Division of Epidemiology, College of Public Health, The Ohio State University, Columbus, OH, USA

    Mark A. Klebanoff & Jonathan L. Slaughter

  7. Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, Columbus, Ohio, USA

    Mark A. Klebanoff

  8. Innovative Infant Feeding Disorders Research Program, Nationwide Children’s Hospital, Columbus, OH, USA

    Sudarshan R. Jadcherla

  9. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA

    Sudarshan R. Jadcherla

  10. Division of Nephrology, Nationwide Children’s Hospital, Columbus, OH, USA

    Tahagod H. Mohamed

Authors
  1. Hibo H. Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carl H. Backes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Molly K. Ball
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria M. Talavera-Barber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark A. Klebanoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sudarshan R. Jadcherla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tahagod H. Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jonathan L. Slaughter
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HHA and JLS designed, analyzed, interpreted, drafted, revised, and approved the final version of the manuscript. CHB, MKB, MMT, MAK, SRJ, and THM interpreted, revised, and approved the final version.

Corresponding author

Correspondence to Jonathan L. Slaughter.

Ethics declarations

Conflict of interest

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdi, H.H., Backes, C.H., Ball, M.K. et al. Prophylactic Indomethacin in extremely preterm infants: association with death or BPD and observed early serum creatinine levels. J Perinatol 41, 749–755 (2021). https://doi.org/10.1038/s41372-021-00995-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-021-00995-x

This article is cited by

Search

Advanced search

Quick links