Glycemic variability is a common complication affecting very preterm infants. Hypoglycemia and hyperglycemia have been associated with increased neonatal morbidities, including retinopathy of prematurity (ROP). However, it remains unclear whether glycemic variability contributes to a higher risk of ROP. Our study investigated the relationship between glycemic variability and severe, treatment-requiring ROP in preterm infants during the first 28 days of life.
Methods
A retrospective case-control study was conducted on infants with a birthweight ≤1500 g and/or gestational age ≤30 weeks. Cases included infants with severe ROP requiring treatment (n = 31) and were matched to controls with no ROP or ROP not requiring treatment (n = 62) in a 1:2 ratio. Glycemic variability was quantified as the standard deviation of mean glucose levels. Statistical analysis included t-tests, chi-squared, and Fisher’s tests, with logistic regression models to adjust for confounders.
Results
Demographics and clinical variables were similar in cases and controls except for ethnicity and PDA. The mean glucose concentration was 130.74 mg/dl (±39.98) in the treatment group and 121.26 mg/dl (±47.44) in controls (p = 0.32). The number of hypo and hyperglycemic episodes was not significantly different between the two groups. Glycemic variability was also similar in cases and controls (mean SD = 36.01 vs 33.45, respectively; p = 0.31). After adjusting for confounders, no association was found between glycemic variability and ROP treatment.
Conclusion
Our study did not identify a significant association between glycemic variability and the development of severe, treatment-requiring ROP.
GoodWVHardyRJDobsonV, et al.Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics2005; 116(1): 15–23. DOI: 10.1542/peds.2004-1413.
2.
AzamiMJaafariZRahmatiS, et al.Prevalence and risk factors of retinopathy of prematurity in Iran: a systematic review and meta-analysis. BMC Ophthalmol2018; 18(1): 83. DOI: 10.1186/s12886-018-0732-3.
3.
FiersonWMAmerican Academy of Pediatrics Section on Ophthalmology, American Academy Of Ophthalmology; American Association For Pediatric Ophthalmology And Strabismus; American Association Of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics2018; 142(6): e20183061. DOI: 10.1542/peds.2018-3061.
4.
Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol2003; 121(12): 1684–1694. DOI: 10.1001/archopht.121.12.1684.
5.
Mintz-HittnerHAKennedyKAChuangAZBEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med2011; 364(7): 603–615. DOI: 10.1056/NEJMoa1007374.
6.
HartnettMEPennJS. Mechanisms and management of retinopathy of prematurity. N Engl J Med2012; 367(26): 2515–2526. DOI: 10.1056/NEJMra1208129.
7.
Kermorvant-DucheminELe MeurGPlaisantF, et al.Thresholds of glycemia, insulin therapy, and risk for severe retinopathy in premature infants: a cohort study. PLoS Med2020; 17(12): e1003477. DOI: 10.1371/journal.pmed.1003477.
8.
JagłaMSzymońskaIStarzecK, et al.Glycemic variability is associated with treatment requiring retinopathy of prematurity: a case-control study. Retina2021; 41(4): 711–717. DOI: 10.1097/IAE.0000000000002949.
9.
JobeAHBancalariE. Bronchopulmonary dysplasia. Am J Respir Crit Care Med2001; 163(7): 1723–1729. DOI: 10.1164/ajrccm.163.7.2011060.
10.
AbmanSHBancalariEJobeA. The evolution of bronchopulmonary dysplasia after 50 years. Am J Respir Crit Care Med2017; 195(4): 421–424. DOI: 10.1164/rccm.201611-2386ED.
11.
PapileLABursteinJBursteinR, et al.Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr1978; 92(4): 529–534. DOI: 10.1016/s0022-3476(78)80282-0.
12.
FlanneryDDEdwardsEMPuopoloKM, et al.Early-onset sepsis among very preterm infants. Pediatrics2021; 148(4): e2021052456. DOI: 10.1542/peds.2021-052456, Epub 2021 Sep 7. Erratum in: Pediatrics. 2022 Oct 1;150(4):e2022059058. doi: 10.1542/peds.2022-059058.
13.
FlanneryDDEdwardsEMCogginsSA, et al.Late-onset sepsis among very preterm infants. Pediatrics2022; 150(6): e2022058813. DOI: 10.1542/peds.2022-058813.
14.
AmbalavananNAucottSWSalavitabarA, et al.Committee on fetus and newborn; section on cardiology and cardiac surgery. Patent ductus arteriosus in preterm infants. Pediatrics2025; 155(5): e2025071425. DOI: 10.1542/peds.2025-071425.
15.
ChiangMFQuinnGEFielderAR, et al.International classification of retinopathy of prematurity, third edition. Ophthalmology2021; 128(10): e51–e68. DOI: 10.1016/j.ophtha.2021.05.031.
16.
BlencoweHLawnJEVazquezT, et al.Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res2013; 74(Suppl 1): 35–49. DOI: 10.1038/pr.2013.205.
17.
RaghuveerTSZackulaR. Strategies to prevent severe retinopathy of prematurity: a 2020 update and meta-analysis. NeoReviews2020; 21(4): e249–e263. DOI: 10.1542/neo.21-4-e249.
18.
StollBJHansenNIBellEF, et al.Eunice Kennedy Shriver national institute of child health and human development neonatal research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA2015; 314(10): 1039–1051. DOI: 10.1001/jama.2015.10244.
19.
CarloWAFinerNNSUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, et al.Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med2010; 362(21): 1959–1969. DOI: 10.1056/NEJMoa0911781.
20.
SmithLE. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Investig Ophthalmol Vis Sci2008; 49(12): 5177–5182. DOI: 10.1167/iovs.08-2584.
21.
KimSJPortADSwanR, et al.Retinopathy of prematurity: a review of risk factors and their clinical significance. Surv Ophthalmol2018; 63(5): 618–637. DOI: 10.1016/j.survophthal.2018.04.002.
22.
DarlowBAHutchinsonJLHenderson-SmartDJ, et al.Australian and New Zealand Neonatal Network. Prenatal risk factors for severe retinopathy of prematurity among very preterm infants of the Australian and New Zealand Neonatal Network. Pediatrics2005; 115(4): 990–996. DOI: 10.1542/peds.2004-1309.
23.
SabriKEllsALLeeEY, et al.Retinopathy of prematurity: a global perspective and recent developments. Pediatrics2022; 150(3): e2021053924. DOI: 10.1542/peds.2021-053924.
24.
Kermorvant-DucheminESapiehaPSirinyanM, et al.Understanding ischemic retinopathies: emerging concepts from oxygen-induced retinopathy. Doc Ophthalmol2010; 120(1): 51–60. DOI: 10.1007/s10633-009-9201-x.
25.
WilliamsBGallacherBPatelH, et al.Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes1997; 46(9): 1497–1503. DOI: 10.2337/diab.46.9.1497.
26.
KimNHJungHHChaDR, et al.Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells. J Endocrinol2000; 165(3): 617–624. DOI: 10.1677/joe.0.1650617.
27.
BrooksSEGuXKaufmannPM, et al.Modulation of VEGF production by pH and glucose in retinal Müller cells. Curr Eye Res1998; 17(9): 875–882. DOI: 10.1076/ceyr.17.9.875.5134.
28.
HaysSPSmithEOSunehagAL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics2006; 118(5): 1811–1818. DOI: 10.1542/peds.2006-0628.
29.
AlexandrouGSkiöldBKarlénJ, et al.Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants. Pediatrics2010; 125(3): e584–e591. DOI: 10.1542/peds.2009-0449.
30.
LeiCDuanJGeG, et al.Association between neonatal hyperglycemia and retinopathy of prematurity: a meta-analysis. Eur J Pediatr2021; 180(12): 3433–3442. DOI: 10.1007/s00431-021-04140-w.
31.
BeardsallKVanhaesebrouckSOgilvy-StuartAL, et al.Validation of the continuous glucose monitoring sensor in preterm infants. Arch Dis Child Fetal Neonatal Ed2013; 98(2): F136–F140. DOI: 10.1136/archdischild-2012-301661.
32.
BeardsallKVanhaesebrouckSOgilvy-StuartAL, et al.A randomised controlled trial of early insulin therapy in very low birth weight infants, “NIRTURE” (neonatal insulin replacement therapy in Europe). BMC Pediatr2007; 7: 29. DOI: 10.1186/1471-2431-7-29.
33.
AuSCTangSMRongSS, et al.Association between hyperglycemia and retinopathy of prematurity: a systemic review and meta-analysis. Sci Rep2015; 5: 9091. DOI: 10.1038/srep09091.
34.
StrawbridgeJCJanzenCChuA, et al.Maternal sociodemographic risk factors for retinopathy of prematurity. Investig Ophthalmol Vis Sci2022; 63(7): 4188.
35.
KarmoutaRAltendahlMRomeroT, et al.Association between social determinants of health and retinopathy of prematurity outcomes. JAMA Ophthalmol2022; 140(5): 496–502. DOI: 10.1001/jamaophthalmol.2022.0667.
36.
HusainSMSinhaAKBunceC, et al.Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity. J Pediatr2013; 163(1): 67–72. DOI: 10.1016/j.jpeds.2012.12.038, Epub 2013 Jan 23. Erratum in: J Pediatr. 2013 Dec;163(6):1798.
37.
FordABeaucheneMStanfordAH, et al.Exposure to persistent hemodynamically significant patent ductus arteriosus is associated with retinopathy of prematurity. J AAPOS2024; 28(3): 103923. DOI: 10.1016/j.jaapos.2024.103923, Epub 2024 Apr 29.
38.
OlowoyeyeAEisenbergRKimM, et al.Factors related to passing the safety fast test among neonates with hypoglycaemia in the neonatal intensive care unit. J Paediatr Child Health2021; 57(4): 507–512. DOI: 10.1111/jpc.15247, Epub 2020 Nov 3.
