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:

Efficacy comparison of 21 interventions to prevent retinopathy of prematurity: a Bayesian network meta-analysis of randomized controlled trials

Eye volume 38, pages 877–884 (2024)Cite this article

Subjects

Abstract

Background

The objective of this study was to evaluate the comparative efficacy of current interventions for the prevention of retinopathy of prematurity (ROP) in premature infants.

Methods

A network meta-analysis (NMA) was performed. We searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library for relevant studies from their inception to May 5, 2022. Publications were eligible for our study if they were randomized controlled trials (RCTs) involving preterm infants at <37 weeks of gestational age and reported the incidence of any-stage ROP treated with the interventions of interest. The overall effect was pooled using the random effects model.

Results

We identified 106 RCTs (involving 23894 participants). This NMA showed that vitamin A supplementation markedly reduced the incidence of ROP, in comparison with placebo (odds ratio [OR] = 0.59, 95% credible interval [95% CrI] 0.33, 0.85), fish oil-based lipid emulsion (OR = 0.57, 95% CrI 0.24, 0.90), early erythropoietin (OR = 0.51, 95% CrI 0.34, 0.98), probiotics (OR = 0.48, 95% CrI 0.32, 0.97), and human milk (OR = 0.50, 95% CrI 0.21, 0.78). Vitamin A supplementation has the highest probability of being the best option for reducing the ROP risk compared with the other 20 interventions based on its surface under the cumulative ranking curve (SUCRA) value (SUCRA = 92.50%, 95% CrI 0.71, 1.00).

Conclusions

Our findings suggest that among 21 interventions, vitamin A supplementation might be the best method of preventing ROP. This NMA offers an important resource for further efforts to develop preventive strategies for ROP.

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
Fig. 2: Radar plot.
Fig. 3: Relative effects of interventions according to the network meta-analysis.
Fig. 4: Results of network meta-analysis using the placebo as the referent intervention.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Fang JL, Sorita A, Carey WA, Colby CE, Murad MH, Alahdab F. Interventions to prevent retinopathy of prematurity: a meta-analysis. Pediatrics. 2016;137:e20153387.

    PubMed  Google Scholar 

  2. Cavallaro G, Filippi L, Bagnoli P, La Marca G, Cristofori G, Raffaeli G, et al. The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge. Acta Ophthalmol. 2014;92:2–20.

    CAS  PubMed  Google Scholar 

  3. Hack M, Wright LL, Shankaran S, Tyson JE, Horbar JD, Bauer CR, et al. Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Network, November 1989 to October 1990. Am J Obstet Gynecol. 1995;172:457–64.

    CAS  PubMed  Google Scholar 

  4. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126:443–56.

    PubMed  Google Scholar 

  5. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001;107:E1.

    CAS  PubMed  Google Scholar 

  6. Li Z, Zhang Y, Liao Y, Zeng R, Zeng P, Lan Y. Comparison of efficacy between anti-vascular endothelial growth factor (VEGF) and laser treatment in Type-1 and threshold retinopathy of prematurity (ROP). BMC Ophthalmol. 2018;18:19.

    PubMed  PubMed Central  Google Scholar 

  7. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2018;1:CD009734.

    PubMed  Google Scholar 

  8. VanderVeen DK, Melia M, Yang MB, Hutchinson AK, Wilson LB, Lambert SR. Anti-vascular endothelial growth factor therapy for primary treatment of type 1 retinopathy of prematurity: a report by the American Academy of Ophthalmology. Ophthalmology. 2017;124:619–33.

    PubMed  Google Scholar 

  9. Wheatley CM, Dickinson JL, Mackey DA, Craig JE, Sale MM. Retinopathy of prematurity: recent advances in our understanding. Br J Ophthalmol. 2002;86:696–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen M, Citil A, McCabe F, Leicht KM, Fiascone J, Dammann CE, et al. Infection, oxygen, and immaturity: interacting risk factors for retinopathy of prematurity. Neonatology. 2011;99:125–32.

    PubMed  Google Scholar 

  11. Fierson WM, Ophthalmology AAOPSo, American Academy Of O, American Association For Pediatric O, Strabismus, American Association Of Certified O. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2018;142:e20183061.

    PubMed  Google Scholar 

  12. Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS. 2013;17:229–34.

    PubMed  PubMed Central  Google Scholar 

  13. Hartnett ME. Pathophysiology and mechanisms of severe retinopathy of prematurity. Ophthalmology. 2015;122:200–10.

    PubMed  Google Scholar 

  14. Hauspurg AK, Allred EN, Vanderveen DK, Chen M, Bednarek FJ, Cole C, et al. Blood gases and retinopathy of prematurity: the ELGAN study. Neonatology. 2011;99:104–11.

    PubMed  Google Scholar 

  15. Lee J, Dammann O. Perinatal infection, inflammation, and retinopathy of prematurity. Semin Fetal Neonatal Med. 2012;17:26–9.

    PubMed  Google Scholar 

  16. Hellstrom A, Hard AL, Engstrom E, Niklasson A, Andersson E, Smith L, et al. Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening. Pediatrics. 2009;123:e638–45.

    PubMed  Google Scholar 

  17. ELFIN trial investigators group. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393:423–33.

    Google Scholar 

  18. Fauchère JC, Koller BM, Tschopp A, Dame C, Ruegger C, Bucher HU. Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr. 2015;167:52–7.e51-3.

    PubMed  Google Scholar 

  19. Sun H, Cheng R, Wang Z. Early vitamin a supplementation improves the outcome of retinopathy of prematurity in extremely preterm infants. Retina. 2020;40:1176–84.

    CAS  PubMed  Google Scholar 

  20. Cota F, Costa S, Giannantonio C, Purcaro V, Catenazzi P, Vento G. Lutein supplementation and retinopathy of prematurity: a meta-analysis. J Matern Fetal Neonatal Med. 2022;35:175–80.

  21. Du Y, He Y, Wang YL, Zhou JG, Chen C. The efficacy and safety of inositol supplementation in preterm infants to prevent retinopathy of prematurity: a systematic review and meta-analysis. BMC Ophthalmol. 2019;19:135.

    PubMed  PubMed Central  Google Scholar 

  22. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. da Costa BR, Pereira TV, Saadat P, Rudnicki M, Iskander SM, Bodmer NS, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021;375:n2321.

    PubMed  PubMed Central  Google Scholar 

  24. Anothaisintawee T, Attia J, Nickel JC, Thammakraisorn S, Numthavaj P, McEvoy M, et al. Management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and network meta-analysis. JAMA. 2011;305:78–86.

    CAS  PubMed  Google Scholar 

  25. Huang J, Wen D, Wang Q, McAlinden C, Flitcroft I, Chen H, et al. Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis. Ophthalmology. 2016;123:697–708.

    PubMed  Google Scholar 

  26. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.

    PubMed  Google Scholar 

  27. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777–84.

    PubMed  Google Scholar 

  28. Hellström A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013;382:1445–57.

    PubMed  PubMed Central  Google Scholar 

  29. Aranda JV, Qu J, Valencia GB, Beharry KD. Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol. 2019;43:360–6.

    PubMed  Google Scholar 

  30. Filippi L, Dal Monte M. A safety review of drugs used for the treatment of retinopathy of prematurity. Expert Opin Drug Saf. 2020;19:1409–18.

    CAS  PubMed  Google Scholar 

  31. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362:1959–69.

    CAS  PubMed  Google Scholar 

  32. Australia B-I, United Kingdom Collaborative G, Tarnow-Mordi W, Stenson B, Kirby A, Juszczak E, et al. Outcomes of two trials of oxygen-saturation targets in preterm infants. N Engl J Med. 2016;374:749–60.

    Google Scholar 

  33. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to systematic review and meta-analysis of prognostic factor studies. BMJ (Clin Res ed). 2019;364:k4597.

    Google Scholar 

  34. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142.

    PubMed  Google Scholar 

  35. Ades AE, Sculpher M, Sutton A, Abrams K, Cooper N, Welton N, et al. Bayesian methods for evidence synthesis in cost-effectiveness analysis. PharmacoEconomics. 2006;24:1–19.

    CAS  PubMed  Google Scholar 

  36. Sutton A, Ades AE, Cooper N, Abrams K. Use of indirect and mixed treatment comparisons for technology assessment. PharmacoEconomics. 2008;26:753–67.

    PubMed  Google Scholar 

  37. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clin Res ed). 2003;327:557–60.

    Google Scholar 

  38. Liang JH, Li J, Wu RK, Li JY, Qian S, Jia RX, et al. Effectiveness comparisons of various psychosocial therapies for children and adolescents with depression: a Bayesian network meta-analysis. Eur Child Adolesc Psychiatry. 2021;30:685–97.

    PubMed  Google Scholar 

  39. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932–44.

    CAS  PubMed  Google Scholar 

  40. Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3:98–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Liang JH, Lu L, Li JY, Qu XY, Li J, Qian S, et al. Contributions of modifiable risk factors to dementia incidence: a Bayesian network analysis. J Am Med Dir Assoc. 2020;21:1592–9.e1513.

    PubMed  Google Scholar 

  42. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ (Clin Res ed). 2005;331:897–900.

    Google Scholar 

  43. Mavridis D, Salanti G. A practical introduction to multivariate meta-analysis. Stat Methods Med Res. 2013;22:133–58.

    PubMed  Google Scholar 

  44. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71.

    PubMed  Google Scholar 

  45. Chaimani A, Salanti G. Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions. Res Synth Methods. 2012;3:161–76.

    PubMed  Google Scholar 

  46. Senjam SS, Chandra P. Retinopathy of prematurity: addressing the emerging burden in developing countries. J Fam Med Prim Care. 2020;9:2600–5.

    Google Scholar 

  47. Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed. 2005;90:F103–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. MacTier H, McCulloch DL, Hamilton R, Galloway P, Bradnam MS, Young D, et al. Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity. J Pediatr. 2012;160:954–9.e951.

    CAS  PubMed  Google Scholar 

  49. Garofoli F, Barilla D, Angelini M, Mazzucchelli I, De Silvestri A, Guagliano R, et al. Oral vitamin A supplementation for ROP prevention in VLBW preterm infants. Ital J Pediatr. 2020;46:77.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ozkan H, Duman N, Kumral A, Kasap B, Ozer EA, Lebe B, et al. Inhibition of vascular endothelial growth factor-induced retinal neovascularization by retinoic acid in experimental retinopathy of prematurity. Physiol Res. 2006;55:267–75.

    CAS  PubMed  Google Scholar 

  51. Tsai AS, Chou HD, Ling XC, Al-Khaled T, Valikodath N, Cole E, et al. Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF). Prog Retin Eye Res. 2021;88:101018.

    PubMed  Google Scholar 

  52. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50:85–91.

    CAS  PubMed  Google Scholar 

  53. Landman J, Sive A, Heese HD, Van der Elst C, Sacks R. Comparison of enteral and intramuscular vitamin A supplementation in preterm infants. Early Hum Dev. 1992;30:163–70.

    CAS  PubMed  Google Scholar 

  54. Darlow BA, Graham PJ. Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants. Cochrane Database Syst Rev. 2000; CD000501.

  55. Zhang S, Zhou R, Li B, Li H, Wang Y, Gu X, et al. Caffeine preferentially protects against oxygen-induced retinopathy. FASEB J. 2017;31:3334–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357:1893–902.

    CAS  PubMed  Google Scholar 

  57. Hussein MA, Coats DK, Khan H, Paysse EA, Steinkuller PG, Kong L, et al. Evaluating the association of autonomic drug use to the development and severity of retinopathy of prematurity. J AAPOS. 2014;18:332–7.

    PubMed  Google Scholar 

  58. Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, et al. Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr. 2010;156:382–7.

    CAS  PubMed  Google Scholar 

  59. Petrucci R, Zollo G, Curulli A, Marrosu G. A new insight into the oxidative mechanism of caffeine and related methylxanthines in aprotic medium: may caffeine be really considered as an antioxidant? Biochim Biophys Acta Gen Subj. 2018;1862:1781–9.

    CAS  PubMed  Google Scholar 

  60. Liu R, Gang L, Shen X, Xu H, Wu F, Sheng L. Binding characteristics and superimposed antioxidant properties of caffeine combined with superoxide dismutase. ACS Omega. 2019;4:17417–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Davis PG. When to start and stop caffeine and why respiratory status matters. Semin Fetal Neonatal Med. 2020;25:101175.

    PubMed  Google Scholar 

  62. Bahji A, Pierce M, Wong J, Roberge JN, Ortega I, Patten S. Comparative efficacy and acceptability of psychotherapies for self-harm and suicidal behavior among children and adolescents a systematic review and network meta-analysis. JAMA Netw Open. 2021;4:e216614.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (82122059) and Suzhou Science and Technology Development Program (SKY2022172).

Author information

Author notes

  1. These authors contributed equally: Miao Zhou, Pei-Chen Duan.

Authors and Affiliations

  1. School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China

    Miao Zhou, Pei-Chen Duan, Dan-Lin Li & Chen-Wei Pan

  2. Department of Ophthalmology, Peking University People’s Hospital, Beijing, China

    Miao Zhou

  3. School of Public Health, Sun Yat-sen University, Guangzhou, China

    Jing-Hong Liang

  4. Department of Ophthalmology, the Affiliated Hospital of Yunnan University, Kunming, China

    Gang Liang

  5. Department of Ophthalmology, Children’s Hospital of Soochow University, Suzhou, China

    Hua Xu

Authors
  1. Miao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pei-Chen Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan-Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing-Hong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hua Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chen-Wei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design of the research: HX, GL, and CWP; Acquisition and interpretation of the data: MZ, PCD, and DLL; Statistical analysis and writing of the manuscript: MZ, PCD, and JHL; Critical revision of the manuscript: HX, GL, and CWP.

Corresponding authors

Correspondence to Hua Xu or Chen-Wei Pan.

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

Zhou, M., Duan, PC., Li, DL. et al. Efficacy comparison of 21 interventions to prevent retinopathy of prematurity: a Bayesian network meta-analysis of randomized controlled trials. Eye 38, 877–884 (2024). https://doi.org/10.1038/s41433-023-02796-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41433-023-02796-2

This article is cited by

Search

Advanced search

Quick links