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:

Cost-effectiveness of probiotics for necrotizing enterocolitis prevention in very low birth weight infants

Journal of Perinatology volume 40, pages 1652–1661 (2020)Cite this article

Subjects

Abstract

Objective

To examine the cost-effectiveness of prophylactic probiotics on necrotizing enterocolitis (NEC) prevention in very low birth weight (VLBW) infants.

Study design

We built a decision-analytic model using TreeAge. Effectiveness was assessed using quality-adjusted life-years (QALY). Primary outcome was an incremental cost-effectiveness ratio (ICER) expressed as cost per QALY gained. Costs were expressed in 2017 US dollars. Deterministic and probabilistic sensitivity analyses (SA) were performed.

Results

For the base case analysis, the ICER of probiotics versus no probiotics for the prevention of NEC in VLBW infants was $1868/QALY. SA revealed that probiotics became cost-saving at a NEC rate of 6.5% and higher or with incremental NEC cost of $37,500 or higher.

Conclusions

Our model demonstrated that prophylactic probiotics were a cost-effective strategy in NEC reduction. SA confirmed that the model is customizable to various clinical settings and thus, can aid in understanding the economic impact of this intervention.

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: One-way SA is a deterministic method that evaluates a variable over a range of values to understand its impact on the ICER.
Fig. 2: Tornado diagram.
Fig. 3: Monte Carlo simulations ICER plot.

Similar content being viewed by others

Code availability

TreeAge Pro Healthcare Version 2020 R1.2 [19] software was used to create the model, generate results, and perform statistical analyses. Model is available upon request. Software requires license for use.

References

  1. Rich BS, Dolgin SE. Necrotizing enterocolitis. Pediatr Rev. 2017;38:552–9.

    Article  PubMed  Google Scholar 

  2. Laughon M, O’Shea MT, Allred EN, Bose C, Kuban K, Van Marter LJ, et al. Chronic lung disease and developmental delay at 2 years of age in children born before 28 weeks’ gestation. Pediatrics. 2009;124:637–48.

    Article  PubMed  Google Scholar 

  3. Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115:696–703.

    Article  PubMed  Google Scholar 

  4. Cassir N, Simeoni U, La Scola B. Gut microbiota and the pathogenesis of necrotizing enterocolitis in preterm neonates. Future Microbiol. 2016;11:273–92.

    Article  CAS  PubMed  Google Scholar 

  5. Sallakh-Niknezhad A, Bashar-Hashemi F, Satarzadeh N, Ghojazadeh M, Sahnazarli G. Early versus late trophic feeding in very low birth weight preterm infants. Iran J Pediatrics. 2012;22:171–6.

    Google Scholar 

  6. Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES. Early enteral feeding and nosocomial sepsis in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2004;89:F289–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hull MA, Fisher JG, Gutierrez IM, Jones BA, Kang KH, Kenny M, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg. 2014;218:1148–55.

    Article  PubMed  Google Scholar 

  8. Stefanescu BM, Gillam-Krakauer M, Stefanescu AR, Markham M, Kosinski JL. Very low birth weight infant care: adherence to a new nutrition protocol improves growth outcomes and reduces infectious risk. Early Hum Dev. 2016;94:25–30.

    Article  PubMed  Google Scholar 

  9. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2018;6:Cd002971.

    PubMed  Google Scholar 

  10. Romaine A, Ye D, Ao Z, Fang F, Johnson O, Blake T, et al. Safety of histamine-2 receptor blockers in hospitalized VLBW infants. Early Hum Dev. 2016;99:27–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014:1–64.

  12. Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sanchez PJ, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009;123:58–66.

    Article  PubMed  Google Scholar 

  13. Sun J, Marwah G, Westgarth M, Buys N, Ellwood D, Gray PH. Effects of probiotics on necrotizing enterocolitis, sepsis, intraventricular hemorrhage, mortality, length of hospital stay, and weight gain in very preterm infants: a meta-analysis. Adv Nutr. 2017;8:749–63.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sekhon MK, Grubb PH, Newman M, Yoder BA. Implementation of a probiotic protocol to reduce rates of necrotizing enterocolitis. J Perinatol. 2019;39:1315–22.

    Article  CAS  PubMed  Google Scholar 

  15. Neu J. Probiotics and necrotizing enterocolitis. Clin Perinatol. 2014;41:967–78.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mowitz ME, Dukhovny D, Zupancic JAF. The cost of necrotizing enterocolitis in premature infants. Semin Fetal Neonatal Med. 2018;23:416–9.

    Article  PubMed  Google Scholar 

  17. Ramsey SD, Willke RJ, Glick H, Reed SD, Augustovski F, Jonsson B, et al. Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report. Value Health. 2015;18:161–72.

    Article  PubMed  Google Scholar 

  18. Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, et al. Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine. JAMA. 2016;316:1093–103.

    Article  PubMed  Google Scholar 

  19. TreeAge Pro Healthcare. R1.2 ed. Williamstown, Massachusetts: TreeAge Software, LLC; 2020. p. https://www.treeage.com/.

  20. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: Final Data for 2017. Natl Vital Stat Rep. 2018;67:1–50.

    PubMed  Google Scholar 

  21. Caro JJ, Briggs AH, Siebert U, Kuntz KM. Modeling good research practices-overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-1. Med Decis Mak. 2012;32:667–77.

    Article  Google Scholar 

  22. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292:2357–65.

    Article  CAS  PubMed  Google Scholar 

  23. Zbinden A, Zbinden R, Berger C, Arlettaz R. Case series of Bifidobacterium longum bacteremia in three preterm infants on probiotic therapy. Neonatology. 2015;107:56–9.

    Article  PubMed  Google Scholar 

  24. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60:S129–34.

    Article  PubMed  PubMed Central  Google Scholar 

  25. van den Nieuwboer M, Claassen E, Morelli L, Guarner F, Brummer RJ. Probiotic and synbiotic safety in infants under two years of age. Beneficial microbes. 2014;5:45–60.

    Article  PubMed  Google Scholar 

  26. Arias E, Xu J. United States Life Tables, 2017. Natl Vital Stat Rep. 2019;68:1–65.

    PubMed  Google Scholar 

  27. Strauss D, Brooks J, Rosenbloom L, Shavelle R. Life expectancy in cerebral palsy: an update. Dev Med Child Neurol. 2008;50:487–93.

    Article  PubMed  Google Scholar 

  28. Saigal S, Ferro MA, Van Lieshout RJ, Schmidt LA, Morrison KM, Boyle MH. Health-related quality of life trajectories of extremely low birth weight survivors into adulthood. J Pediatr. 2016;179:68–73.e61.

    Article  PubMed  Google Scholar 

  29. Purchasing Power Parity. Accessed 9 Feb 2019. https://data.worldbank.org/indicator/PA.NUS.PPP.

  30. Consumer Price Index. Accessed 11 June 2020. https://www.bls.gov/cpi/data.htm.

  31. Evivo (R). 2019. https://www.evivo.com/shop/healthcare-use.

  32. Phibbs CS, Schmitt SK, Cooper M, Gould JB, Lee HC, Profit J, et al. Birth hospitalization costs and days of care for mothers and neonates in california, 2009–2011. J Pediatr. 2019;204:118–125.e114.

    Article  PubMed  Google Scholar 

  33. Honeycutt A, Dunlap L, Chen H. al Homsi, G. Economic costs associated with mental retardatio n, cerebral palsy, hearing loss, and vision impairment-United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:57–9.

  34. Johnson TJ, Patel AL, Jegier BJ, Engstrom JL, Meier PP. Cost of morbidities in very low birth weight infants. J Pediatr. 2013;162:243–9.e241.

    Article  PubMed  Google Scholar 

  35. Cameron D, Ubels J, Norström F. On what basis are medical cost-effectiveness thresholds set? Clashing opinions and an absence of data: a systematic review. Glob health action. 2018;11:1447828.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Drummond MFSM, Claxton K, Stoddart GL, Torrance GW. Methods for the economic evaluation of health care programmes, 4th edn. New York, NY: Oxford University Press; 2015.

  37. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness-the curious resilience of the $50,000-per-QALY threshold. N. Engl J Med. 2014;371:796–7.

    Article  CAS  PubMed  Google Scholar 

  38. Leal JR, Heitman SJ, Conly JM, Henderson EA, Manns BJ. Cost-effectiveness analysis of the use of probiotics for the Prevention of Clostridium difficile-associated diarrhea in a provincial healthcare system. Infect Control Hosp Epidemiol. 2016;37:1079–86.

    Article  PubMed  Google Scholar 

  39. Li N, Zheng B, Cai HF, Chen YH, Qiu MQ, Liu MB. Cost-effectiveness analysis of oral probiotics for the prevention of Clostridium difficile-associated diarrhoea in children and adolescents. J Hosp Infect. 2018;99:469–74.

    Article  CAS  PubMed  Google Scholar 

  40. Trang S, Zupancic JAF, Unger S, Kiss A, Bando N, Wong S, et al. Cost-effectiveness of supplemental donor milk versus formula for very low birth weight infants. Pediatrics 2018;141:1–10.

    Article  Google Scholar 

  41. Ganapathy V, Hay JW, Kim JH. Costs of necrotizing enterocolitis and cost-effectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed Med. 2012;7:29–37.

    Article  PubMed  Google Scholar 

  42. Hampson G, Roberts SLE, Lucas A, Parkin D. An economic analysis of human milk supplementation for very low birth weight babies in the USA. BMC Pediatr. 2019;19:337.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Cole CR, Hansen NI, Higgins RD, Ziegler TR, Stoll BJ. Very low birth weight preterm infants with surgical short bowel syndrome: incidence, morbidity and mortality, and growth outcomes at 18 to 22 months. Pediatrics. 2008;122:e573–82.

    Article  PubMed  Google Scholar 

  44. Duro D, Kalish LA, Johnston P, Jaksic T, McCarthy M, Martin C, et al. Risk factors for intestinal failure in infants with necrotizing enterocolitis: a Glaser Pediatric Research Network study. J Pediatr. 2010;157:203–8.e201.

    Article  PubMed  PubMed Central  Google Scholar 

  45. The Patient Protection and Affordable Care Act. 2010. https://www.govinfo.gov/content/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf.

  46. Glick HA, McElligott S, Pauly MV, Willke RJ, Bergquist H, Doshi J, et al. Comparative effectiveness and cost-effectiveness analyses frequently agree on value. Health Aff. 2015;34:805–11.

    Article  Google Scholar 

  47. Horbar JD, Edwards EM, Greenberg LT, Morrow KA, Soll RF, Buus-Frank ME, et al. Variation in performance of neonatal intensive care units in the United States. JAMA pediatrics. 2017;171:e164396.

    Article  PubMed  Google Scholar 

  48. Flanagan P, Tigue PM, Perrin J. The value proposition for pediatric care. JAMA Pediatrics. 2019;173:1125–6.

    Article  PubMed  Google Scholar 

  49. Dukhovny D, Pursley DM, Kirpalani HM, Horbar JH, Zupancic JA. Evidence, quality, and waste: solving the value equation in neonatology. Pediatrics. 2016;137:e20150312.

    Article  PubMed  Google Scholar 

  50. NEC Society: Building a World Without NEC. https://necsociety.org/.

Download references

Acknowledgements

We would like to thank Dr. Ciaran Phibbs for sharing detailed data from the California cost data project for optimal model input [32].

Author information

Authors and Affiliations

  1. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    Atoosa F. Craighead & Dmitry Dukhovny

  2. Department of Neonatal and Newborn Medicine, Kaiser Roseville Medical Center, Roseville, CA, USA

    Atoosa F. Craighead

  3. Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA

    Aaron B. Caughey & Alyssa R. Hersh

  4. Department of Economics, San Francisco State University, San Francisco, CA, USA

    Anoshua Chaudhuri

  5. Fetal and Neonatal Institute, Division of Neonatology, Children’s Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Leah Yieh

Authors
  1. Atoosa F. Craighead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron B. Caughey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anoshua Chaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leah Yieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alyssa R. Hersh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dmitry Dukhovny
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AFC: conceptualized and designed the work, drafted the initial manuscript, created the tables and figures, and critically reviewed and revised the manuscript. ABC: contributed to the study design, data analysis, and interpretation of data, and critically reviewed and revised the manuscript. AC: provided feedback about the study design, data interpretation, and critically reviewed and revised the manuscript. LY: contributed to the study design, data analysis, and interpretation of data, and critically reviewed and revised the manuscript. AH: contributed to the study design, data analysis, interpretation of data, and assisted in creation of tables and figures, and critically reviewed and revised the manuscript. DD: conceptualized and designed the work, provided feedback about the study design, helped draft the initial manuscript, assisted in the creation of the tables and figures, and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Atoosa F. Craighead.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Craighead, A.F., Caughey, A.B., Chaudhuri, A. et al. Cost-effectiveness of probiotics for necrotizing enterocolitis prevention in very low birth weight infants. J Perinatol 40, 1652–1661 (2020). https://doi.org/10.1038/s41372-020-00790-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-020-00790-0

This article is cited by

Search

Advanced search

Quick links