Thresholds Of Glycemia, Insulin Therapy, And Risk For Severe Retinopathy In Premature Infants: A Cohort Study

BackgroundHyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants.Methods and findingsIn 2 independent, monocentric cohorts of preterm infants born at <30 weeks' gestation (Nantes University Hospital, 2006-2016, primary, and Lyon-HFME University Hospital, 2009-2017, validation), we first analyzed the association between severe (stage 3 or higher) ROP and 2 markers of glucose exposure between birth and day 21-maximum value of glycemia (MaxGly(1-21)) and mean of daily maximum values of glycemia (MeanMaxGly(1-21))-using logistic regression models. In both the primary (n = 863 infants, mean gestational age 27.5 +/- 1.4 weeks, boys 52.5%; 38 with severe ROP; 54,083 glucose measurements) and the validation cohort (n = 316 infants, mean gestational age 27.4 +/- 1.4 weeks, boys 51.3%), MaxGly(1-21) and MeanMaxGly(1-21) were significantly associated with an increased risk of severe ROP: odds ratio (OR) 1.21 (95% CI 1.14-1.27, p < 0.001) and OR 1.70 (95% CI 1.48-1.94, p < 0.001), respectively, in the primary cohort and OR 1.17 (95% CI 1.05-1.32, p = 0.008) and OR 1.53 (95% CI 1.20-1.95, p < 0.001), respectively, in the validation cohort. These associations remained significant after adjustment for confounders in both cohorts. Second, we identified optimal cutoff values of duration of exposure above each concentration of glycemia between 7 and 13 mmol/l using receiver operating characteristic curve analyses in the primary cohort. Optimal cutoff values for predicting stage 3 or higher ROP were 9, 6, 5, 3, 2, 2, and 1 days above a glycemic threshold of 7, 8, 9, 10, 11, 12, and 13 mmol/l, respectively. Severe exposure was defined as at least 1 exposure above 1 of the optimal cutoffs. Severe ROP was significantly more common in infants with severe exposure in both the primary (10.9% versus 0.6%, p < 0.001) and validation (5.2% versus 0.9%, p = 0.030) cohorts. Finally, we analyzed the association between insulin therapy and severe ROP in a national population-based prospectively recruited cohort (EPIPAGE-2, 2011, n = 1,441, mean gestational age 27.3 +/- 1.4, boys 52.5%) using propensity score weighting. Insulin use was significantly associated with severe ROP in overall cohort crude analyses (OR 2.51 [95% CI 1.13-5.58], p = 0.024). Adjustment for inverse propensity score (gestational age, sex, birth weight percentile, multiple birth, spontaneous preterm birth, main pregnancy complications, surfactant therapy, duration of oxygen exposure between birth and day 28, digestive state at day 7, caloric intake at day 7, and highest glycemia during the first week) and duration of oxygen therapy had a large but not significant effect on the association between insulin treatment and severe ROP (OR 0.40 [95% CI 0.13-1.24], p = 0.106). Limitations of this study include its observational nature and, despite the large number of patients included compared to earlier similar studies, the lack of power to analyze the association between insulin use and retinopathy.ConclusionsIn this study, we observed that exposure to high glucose concentration is an independent risk factor for severe ROP, and we identified cutoff levels that are significantly associated with increased risk. The clinical impact of avoiding exceeding these thresholds to prevent ROP deserves further evaluation.Author summaryWhy was this study done?Hyperglycemia, i.e., elevated blood glucose, is common in preterm babies, due to the immaturity of glucose regulation mechanisms; it is often treated with insulin infusion, based on weak evidence.A number of studies, with heterogeneity in both setting and design, have suggested that hyperglycemia may be associated with increased risk of morbidity in premature infants, especially severe retinopathy of prematurity, a condition characterized by an abnormal development of the retinal vessels that can lead to blindness.However, current published evidence does not rule out that hyperglycemia may only be a marker of severity of illness and not an independent risk factor for retinopathy of prematurity because not all potential confounding factors were taken into account.It is also uncertain which concentration of blood glucose could be associated with tissue damage in preterm infants, with little consensus on the cutoff level to treat hyperglycemia.What did the researchers do and find?We used 2 independent cohorts of 863 (primary cohort) and 316 (validation cohort) preterm infants born atWe used a third cohort-a prospective, nationwide population-based cohort of 1,441 preterm infants born at <30 weeks' gestation, representing a large variation of practices regarding neonatal management-to examine the impact of strategies to avoid or reduce hyperglycemia on the risk of severe retinopathy of prematurity.Strengthened by multiple sensitivity analyses and external validation, our results support the hypothesis that hyperglycemia is an independent risk factor for severe retinopathy of prematurity and not a mere marker of illness.More importantly, we identified thresholds of combined severity and duration of hyperglycemia above which the risk of severe retinopathy increases significantly.In the nationwide population-based cohort, the analysis of insulin as a protective factor against severe retinopathy of prematurity found a large but not significant effect after controlling for confounding factors.What do these findings mean?The results suggest that overall average exposure and duration of hyperglycemia matter more than a single high glucose value when determining risk of retinopathy.The thresholds of combined severity and duration of exposure that were identified may help physicians to determine treatment strategies in hyperglycemic premature infants.The clinical impact of avoiding exceeding these thresholds to prevent severe retinopathy of prematurity deserves evaluation.