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.

  • Original Article
  • Published:

Hyperglycemia and Retinopathy of Prematurity in Very Low Birth Weight Infants

Journal of Perinatology volume 23, pages 186–194 (2003)Cite this article

Abstract

OBJECTIVE: Retinopathy of prematurity (ROP) remains a leading cause of morbidity in the very low-birth-weight (VLBW) infant. This study investigates a possible association between serum/blood glucose and the development of ROP.

METHODS: A retrospective case–control study of all infants born between 1992 and 1997 at the Johns Hopkins Hospital with birth weights less than 1000 g who developed Stage 3 or 4 ROP was conducted. Controls either had Stage 1 ROP or no eye disease and were matched 2:1 with ROP patients for gestational age, birth weight and year of birth. Odds ratios (ORs) of ROP were calculated for multiple exposures over the first month after birth, including oxygen concentration (FiO2), blood glucose levels, vitamin E, mean airway pressure and mean blood pressure.

RESULTS: In a simple logistic regression analysis, we found an increased ROP risk for: (1) each 10 mg/dl increase of mean glucose (OR 1.96; 95% CI 1.13 to 3.42), (2) each 1% increase of mean FiO2 (OR 1.06; 95% CI 1.004 to 1.13), (3) history of dopamine infusion (OR 5.4; 95% CI 1.16 to 25.2) and (4) intraventricular hemorrhage Grade 3 or 4 (OR 7.3; 95% CI 1.53 to 34.7). Using a multiple regression model, we found an increased ROP risk for each 10 mg/dl increase of mean glucose (OR 2.7; 95% CI 1.003 to 7.27). Each IU/kg/day of vitamin E supplementation reduced ROP risk (OR 0.37; 95% CI 0.16–0.86).

CONCLUSION: In this study, we could demonstrate that glucose levels in the first month of life are associated with the development of ROP. Further studies have to determine if this association is causal or if hyperglycemia is just an expression of severity of illness.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Pierce EA, Mukai S . Controversies in the management of retinopathy of prematurity. Int Ophthalmol Clin 1994;34:121–148 (Review).

    Article  CAS  Google Scholar 

  2. Patz A, Hoeck LE, DeLaCruz E . Studies on the effect of high oxygen administration in retrolental fibroplasia. Am J Ophthalmol 1952;35:1248–1252.

    Article  CAS  Google Scholar 

  3. Chan-Ling T, Tout S, Hollander H, Stone J . Vascular changes and their mechanisms in the feline model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1992;33:2128–2147.

    CAS  PubMed  Google Scholar 

  4. Holmes JM, Zhang S, Leske DA, Lanier WL . The effect of carbon dioxide on oxygen-induced retinopathy in the neonatal rat. Curr Eye Res 1997;16:725–732.

    Article  CAS  Google Scholar 

  5. Holmes JM, Zhang S, Leske DA, Lanier WL . Carbon dioxide-induced retinopathy in the neonatal rat. Curr Eye Res. 1998;17:608–616.

    Article  CAS  Google Scholar 

  6. Shohat M, Reisner SH, Krikler R, Nissenkorn I, Yassur Y, Ben-Sira I . Retinopathy of prematurity: Incidence and risk factors. Pediatrics 1983;72:159–163.

    CAS  PubMed  Google Scholar 

  7. Bassiouny MR . Risk factors associated with retinopathy of prematurity: A study from Oman. J Trop Pediatr 1996;42:355–358.

    Article  CAS  Google Scholar 

  8. Cats BP, Tan KE . Retinopathy of prematurity: review of a four-year period. Br J Ophthalmol 1985;69:500–503.

    Article  CAS  Google Scholar 

  9. Mittal M, Dhanireddy R, Higgins RD . Candida sepsis and association with retinopathy of prematurity. Pediatrics. 1998;101:654–657.

    Article  CAS  Google Scholar 

  10. Sacks LM, Schaffer DB, Anday EK, Peckham GJ, Delivoria-Papadopoulos M . Retrolental fibroplasia and blood transfusion in very low-birth-weight infants. Pediatrics 1981;68:770–774.

    CAS  PubMed  Google Scholar 

  11. Procianoy RS, Garcia-Prats JA, Hittner HM, Adams JM, Rudolph AJ . An association between retinopathy of prematurity and intraventricular hemorrhage in very low birth weight infants. Acta Paediatr Scand 1981;70:473–477.

    Article  CAS  Google Scholar 

  12. Raju TN, Langenberg P, Bhutani V, Quinn GE . Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials. J Pediatr 1997;131:844–850.

    Article  CAS  Google Scholar 

  13. Ramanathan R, Siassi B, deLemos RA . Severe retinopathy of prematurity in extremely low birth weight infants after short-term dexamethasone therapy. J Perinatol 1995;15:178–182.

    CAS  PubMed  Google Scholar 

  14. Haroon Parupia MF, Dhanireddy R . Association of postnatal dexamethasone use and fungal sepsis in the development of severe retinopathy of prematurity and progression to laser therapy in extremely low-birth-weight infants. J Perinatol 2001;21(4):242–247.

    Article  CAS  Google Scholar 

  15. Atherton A, Hill DW, Keen H, Young S, Edwards EJ . The effect of acute hyperglycaemia on the retinal circulation of the normal cat. Diabetologia 1980;18:233–237.

    Article  CAS  Google Scholar 

  16. Sullivan PM, Davies GE, Caldwell G, Morris AC, Kohner EM . Retinal blood flow during hyperglycemia. A laser Doppler velocimetry study. Invest Ophthalmol Vis Sci 1990;31:2041–2045.

    CAS  PubMed  Google Scholar 

  17. Ando J, Nomura H, Kamiya A . The effect of fluid shear stress on the migration and proliferation of cultured endothelial cells. Microvasc Res 1987;33:62–70.

    Article  CAS  Google Scholar 

  18. Binder ND, Raschko PK, Benda GI, Reynolds JW . Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia. J Pediatr 1989;114: 273–280.

    Article  CAS  Google Scholar 

  19. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Pediatrics 1984;74:127–133.

  20. Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA . Score for Neonatal Acute Physiology: A physiologic severity index for neonatal intensive care. Pediatrics 1993;91:617–623.

    CAS  PubMed  Google Scholar 

  21. Cornblath M, Wybregt SH, Baens GS . Studies of carbohydrate metabolism in the newborn Infant. VII. Tests of carbohydrate tolerance in premature infants. Pediatrics 1963;32:1007–1024.

    CAS  PubMed  Google Scholar 

  22. Kinsey VE, Jacobus JT, Hemphill FM . Retrolental fibroplasia: cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol 1956;56:481–487.

    Article  CAS  Google Scholar 

  23. Valentine PH, Jackson JC, Kalina RE, Woodrum DE . Increased survival of low birth weight infants: impact on the incidence of retinopathy of prematurity. Pediatrics 1989;84:442–445.

    CAS  PubMed  Google Scholar 

  24. Gibson DL, Sheps SB, Schechter MT, Wiggins S, McCormick AQ . Retinopathy of prematurity: A new epidemic? Pediatrics 1989;83:486–492.

    CAS  PubMed  Google Scholar 

  25. Lucey JF, Dangman B . A reexamination of the role of oxygen in retrolental fibroplasia. Pediatrics 1984;73:82–96 (Review).

    CAS  PubMed  Google Scholar 

  26. Flynn JT, Bancalari E, Bawol R, et al. Retinopathy of prematurity. A randomized, prospective trial of transcutaneous oxygen monitoring. Ophthalmology 1987;94:630–638.

    Article  CAS  Google Scholar 

  27. Gilmour CH, Sentipal-Walerius JM, Jones JG, et al. Pulse dexamethasone does not impair growth and body composition of very low birth weight infants. J Am Coll Nutr 1995;14:455–462.

    Article  CAS  Google Scholar 

  28. Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 1998;17:593–598.

    Article  CAS  Google Scholar 

  29. Duh E, Aiello LP . Vascular endothelial growth factor and diabetes: The agonist versus antagonist paradox. Diabetes 1999;48:1899–1906 (Review).

    Article  CAS  Google Scholar 

  30. Nathan DM . The pathophysiology of diabetic complications: How much does the glucose hypothesis explain? Ann Intern Med 1996;124:86–89 (Review).

    Article  CAS  Google Scholar 

  31. Perlman M, Claris O, Hao Y, et al. Secular changes in the outcomes to eighteen to twenty-four months of age of extremely low birth weight infants, with adjustment for changes in risk factors and severity of illness. J Pediatr 1995;126:75–87.

    Article  CAS  Google Scholar 

  32. Pildes RS . Neonatal hyperglycemia. J Pediatr 1986;109:905–907 (Review).

    Article  CAS  Google Scholar 

  33. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE . Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg 1969;169:974–984.

    Article  CAS  Google Scholar 

  34. Mamunes P, Baden M, Bass JW, Nelson J . Early intravenous feeding of the low birth weight neonate. Pediatrics 1969;43:241–250.

    CAS  PubMed  Google Scholar 

  35. Phelps DL . Retinopathy of prematurity. Pediatr Rev 1995;16:50–56 (Review).

    Article  CAS  Google Scholar 

  36. Schlebusch H, Niesen M, Sorger M, Paffenholz I, Fahnenstich H . Blood glucose determinations in newborns: Four instruments compared. Pediatr Pathol Lab Med 1998;18:41–48.

    Article  CAS  Google Scholar 

  37. Kohner EM, Patel V, Rassam SM . Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes 1995;44:603–607 (Review).

    Article  CAS  Google Scholar 

  38. Tiedeman JS, Kirk SE, Srinivas S, Beach JM . Retinal oxygen consumption during hyperglycemia in patients with diabetes without retinopathy. Ophthalmology. 1998;105:31–36.

    Article  CAS  Google Scholar 

  39. Cabanas F, Pellicer A, Garcia-Alix A, Quero J, Stiris TA . Effect of dexamethasone therapy on cerebral and ocular blood flow velocity in premature infants studied by colour Doppler flow imaging. Eur J Pediatr 1997;156:41–46.

    Article  CAS  Google Scholar 

  40. Aiello LP . Vascular endothelial growth factor and the eye: biochemical mechanisms of action and implications for novel therapies. Ophthalmic Res 1997;29:354–362 (Review).

    Article  CAS  Google Scholar 

  41. Stone J, Chan-Ling T, Pe'er J, Itin A, Gnessin H, Keshet E . Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1996;37:290–299.

    CAS  PubMed  Google Scholar 

  42. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE . Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal. Proc Natl Acad Sci USA 1995;92:905–909.

    Article  CAS  Google Scholar 

  43. Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145:574–584.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Brooks SE, Gu X, Kaufmann PM, Marcus DM, Caldwell RB . Modulation of VEGF production by pH and glucose in retinal Muller cells. Curr Eye Res 1998;17:875–882.

    Article  CAS  Google Scholar 

  45. Kim NH, Jung HH, Cha DR, Choi DS . Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells. J Endocrinol 2000;165:617–624.

    Article  CAS  Google Scholar 

  46. Hellstrom A, Perruzzi C, Ju M . et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA 2001;98:5804–5808.

    Article  CAS  Google Scholar 

  47. Higgins RD, Mendelsohn AL, DeFeo MJ, Ucsel R, Hendricks-Munoz KD . Antenatal dexamethasone and decreased severity of retinopathy of prematurity. Arch Ophthalmol 1998;116:601–605.

    Article  CAS  Google Scholar 

  48. Muller DP . Vitamin E therapy in retinopathy of prematurity. Eye 1992;6:221–225 (Review).

    Article  Google Scholar 

  49. Finer NN, Peters KL, Hayek Z, Merkel CL . Vitamin E and necrotizing enterocolitis. Pediatrics 1984;73:387–393.

    CAS  PubMed  Google Scholar 

  50. Johnson L, Bowen Jr FW, Abbasi S, et al. Relationship of prolonged pharmacologic serum levels of vitamin E to incidence of sepsis and necrotizing enterocolitis in infants with birth weight 1,500 grams or less. Pediatrics 1985;75:619–638.

    CAS  PubMed  Google Scholar 

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

  52. Cooke RW, Clark D, Hickey-Dwyer M, Weindling AM . The apparent role of blood transfusions in the development of retinopathy of prematurity. Eur J Pediatr 1993;152:833–836.

    Article  CAS  Google Scholar 

  53. Hesse L, Eberl W, Schlaud M, Poets CF . Blood transfusion. Iron load and retinopathy of prematurity. Eur J Pediatr 1997;156:465–470.

    Article  CAS  Google Scholar 

  54. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA . High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. J Pediatr 1997;131:541–544.

    Article  CAS  Google Scholar 

  55. Brooks SE, Marcus DM, Gillis D, Pirie E, Johnson CS, Bhatia J . The effect of blood transfusion protocol on retinopathy of prematurity: A prospective, randomized study. Pediatrics 1999;104:514–518.

    Article  CAS  Google Scholar 

  56. Dweck HS, Cassady G . Glucose intolerance in infants of very low birth weight. I. Incidence of hyperglycemia in infants of birth weights 1,100 grams or less. Pediatrics 1974;53:189–195.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Ms. Eileen Wade for her help in collecting data and to Dr. Marvin Cornblath for his critical review of this manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ruchira Garg MD

  2. Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alexander G Agthe MD, Pamela K Donohue ScD, MS, PA-C & Christoph U Lehmann MD

Authors
  1. Ruchira Garg MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander G Agthe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela K Donohue ScD, MS, PA-C
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christoph U Lehmann MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garg, R., Agthe, A., Donohue, P. et al. Hyperglycemia and Retinopathy of Prematurity in Very Low Birth Weight Infants. J Perinatol 23, 186–194 (2003). https://doi.org/10.1038/sj.jp.7210879

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jp.7210879

This article is cited by

Search

Advanced search

Quick links