Retinopathy of prematurity (ROP) constitutes a significant morbidity in premature infants that can lead to blindness. Multiple retrospective studies have identified neonatal hyperglycemia as a risk for developing ROP. However, in the absence of any reported prospective study, it is not clear whether hyperglycemia is associated with ROP independent of the commonly associated comorbidities. The objective of this study was to investigate whether hyperglycemia in premature infants is independently associated with ROP.
Premature infants (<1500 g or⩽32 weeks gestational age) were enrolled in a prospective longitudinal cohort study. All demographic, clinical and laboratory data were collected. Bedside whole-blood glucose concentration was measured every 8 h daily for 7 days. For any glucose reading<50 or>150 mg dl−1, serum sample was sent to the laboratory for confirmation. Hyperglycemia was defined as any blood glucose level⩾150 mg dl−1. ROP patients were compared with non-ROP patients in a bivariate analysis. Variables significantly associated with ROP were studied in a logistic regression model.
A total of 65 patients were enrolled with gestational age 31.1±1.2 weeks and birth weight 1385±226 g. Thirty-one patients (48%) were identified with hyperglycemia. On eye examination, 19 cases (29.2%) had ROP (13 with stage 1, 4 with stage 2 and 2 with stage 3). There were more cases of ROP in the hyperglycemia group compared with the euglycemia group (45% vs 15%, P=0.007). Patients who developed ROP had significantly higher maximum and average glucose concentrations when compared with non-ROP patients. Multiple factors have been associated with ROP on bivariate analysis, including gestational age, exposure to oxygen, respiratory support and poor weight gain. However, in a logistic regression model including all significant variables, average blood glucose in the first week of life was the factor independently associated with ROP with an odds ratio of: 1.77 (95% confidence interval: 1.08 to 2.86), P=0.024.
In a cohort of premature infants, elevated average blood glucose concentrations in the first week of life is independently associated with the development of ROP.
Hyperglycemia is a significant risk factor for morbidity and mortality in preterm infants. There are multiple physiological and biochemical mechanisms in preterm infants that can lead to excess glucose production, insulin resistance or glucose intolerance; the sequelae of these disturbances in glucose metabolism are extensive.1,2 Hyperglycemia could be associated with osmotic diuresis and dehydration, which increase the risk of cerebral bleeding and electrolyte imbalance. There are also concerns that it may be associated with increased mortality and other morbidities, such as decreased immunity, increased infection, poor wound healing and loss of skeletal and cardiac muscles.3,4
Retinopathy of prematurity (ROP) remains a leading cause of morbidity in very low birth weight infants.5 The provision of supplemental oxygen, while a major risk factor, is not the only cause of the disease as demonstrated by a series of low birth weight infants who developed ROP without ever receiving any oxygen.6 Other proposed risks for the development of ROP include poor postnatal growth,7,8 hypoxia,9 hypercarbia,10 hypocarbia,11 exposure to prolonged and aggressive mechanical ventilation,12 inotrope therapy,6 postnatal steroids,13,14 prolonged hyperalimentation,15,16 blood transfusions11,17 and vitamin E deficiency.18 Moreover, ROP has been associated with the presence of patent ductus arteriosus,19 bronchopulmonary dysplasia,19 sepsis,16,20 systemic candidiasis21 and intraventricular hemorrhage.22
Several retrospective studies have recently suggested hyperglycemia as a possible risk factor for ROP.23, 24, 25, 26, 27 Hyperglycemia is commonly associated with many conditions in very low birth weight infant, including sepsis, candidiasis, intraventricular hemorrhage and postnatal steroids, all of which are frequently encountered in infants who later develop ROP.23 Meanwhile, it is quite plausible that hyperglycemia imposes biological changes to the retina; adults with poorly controlled diabetes develop a distinct neoproliferative retinopathy that is particularly identified in patients with elevated serum glucose over prolonged periods.28 There has been a consensus agreement for the need to prospectively test the association of hyperglycemia with ROP.29, 30, 31 To the best of our knowledge, we are not aware of any prospective study to address such an association that is critically important, especially with the growing interest in early and aggressive parenteral nutrition. The aim of this prospective cohort study was to determine whether elevated glucose concentration is an independent risk factor for the development of ROP in premature infants.
We conducted a prospective cohort study on premature neonates admitted to the neonatal intensive care unit (NICU) at Cairo University Children’s Hospital, which is the largest referral tertiary care unit in the country. Infants were included in the study if admitted within 24 h of life with gestational age (GA)⩽32 weeks or birth weight<1500 g. Infants with major congenital anomalies were excluded from the study. The study was approved by the ethics committee and was conducted in accordance with the University bylaws for human research. Parental consents were obtained for all subjects.
Full maternal and perinatal history was collected for all the studied neonates. Other NICU data such as the use of oxygen, ventilation and phototherapy were documented. Data on date of start and day of full establishment of enteral feeds, type of feeding and full caloric intake were recorded.
Fundus examination was initially done at 4 to 6 weeks in compliance with the recommendations of American Academy of Pediatrics.32 Follow-up examinations were scheduled during the NICU stay and after hospital discharge as based on retinal findings. Examinations were performed by experienced pediatric ophthalmologists while masked to the glycemia condition of the infants. Retinal examination was done using binocular indirect ophthalmoscope, lid speculum and scleral depressors. Before examination, proper dilation of the pupil was performed using a topical anesthetic followed by an eye drop combination (0.2% cyclopentolate and 1% phenylephrine). Stages of severity and the zones for the extent of ROP were categorized by the lowest zone and the highest stage observed in each eye using the international classification of ROP.33,34
Routine laboratory investigations were obtained from all cases, including complete blood picture, blood chemistry and blood gases. In addition, glucose concentration was checked using point-of-care glucometer (Optuim Xceed, Abbott, lake Forest, IL, USA). Glucose concentration was then measured on admission every 8 h daily for 7 days. For any glucose reading<50 or>150 mg dl−1, serum sample was sent to the laboratory for confirmation. Only glucose concentrations in samples collected every 8 h were used in analysis. Based on whether plasma glucose concentrations were ever>150 mg dl−1, infants were stratified into two groups: hyperglycemia group and euglycemia group. Hyperglycemic was managed in all the subjects by decreasing glucose infusion. None of the study infants received insulin. Hypoglycemia was defined as blood glucose<50 mg dl−1.
Data were coded and double entry was done to check validity. Data were analyzed using the SPSS (Statistical Package for the Social Science, Chicago, IL, USA) version 18. Data were summarized using mean, s.d. and range for continuous variables and percentage for categorical variables. Comparisons between groups were done using t-test for continuous variables and chi-squared test for categorical variables. Logistic regression model was used to test the association of hyperglycemia and ROP while controlling for confounding variables. P-values<0.05 were considered as statistically significant.
Previous studies showed a 40% to 50% difference in ROP in hyperglycemic vs euglycemic patients.24,29 With the presumption of a 30% difference in ROP between hyperglycemia and euglycemia, and an estimated incidence of hyperglycemia in 50% of preterm infants in our study, a sample size of 60 would be adequate to detect such difference (power=80% and α=0.05).
The study was conducted on 65 preterm neonates admitted to the NICU in Cairo University during a period of 6 months; out of the 65 enrolled subjects, 31 (48%) were hyperglycemic. The euglycemia and hyperglycemia groups did not differ in gestational age, birth weight or mode of delivery. Infants in the hyperglycemia group were more likely to be females, had greater acuity of illness using the Clinical Risk Index for Babies Score, with medians (ranges) of 1 (0 to 6) vs 2 (0 to 7), P=0.001, and received more frequent red cell transfusions (Table 1). In the hyperglycemia group, there was no significant difference between the mean bedside glucose vs serum laboratory testing; 267.6±101.2 vs 250±86.4 mg dl−1, P=0.46.
Forty-six infants (70.8%) had normal fundus examination, while 19 cases (29.2%) had ROP. Out of the 19 ROP cases, 13 had stage-1, 4 infants had stage-2, and 2 infants had stage-3. Compared with non-ROP infants (n=46), cases with ROP (n=19) were significantly of younger gestational age (P<0.001), smaller birth weight (P<0.001), more likely to have respiratory distress (P=0.001) and exposed to phototherapy (P=0.007). Maternal and neonatal factors associated with ROP are presented in Table 2.
There were more cases of ROP in the hyperglycemia group compared with the euglycemia group (45% vs 15%, P=0.007), odds ratio 4.776 (95% confidence interval (CI): 1.46 to 15.60). Figure 1 presents average daily glucose concentrations in infants with and without ROP during the first week of life. Mean, maximum and minimum values for glucose concentrations in ROP and non-ROP infants are shown in Table 3. Infants with ROP had significantly higher average and maximum glucose values. Hypoglycemia was detected in 13 (20%) of the studied population. The incidence of ROP in infants with hypoglycemia was 15%, whereas ROP in non-hypoglycemic patients was 33%; this difference was not significant (P=0.315).
Duration of respiratory support (continuous positive airway pressure or mechanical ventilation), duration of oxygen therapy and the concentration of the administered oxygen (FiO2) during the first 3 days were all significantly higher in ROP cases (Table 4). Compared with non-ROP infants, infants who developed ROP had delayed onset to introduce enteral feeds (7.6±4.5 vs 5±3.4 days, P=0.01), to reach full enteral feed (25.1±6.3 vs 20.2±7.8 days, P=0.008) and gained less weight (P=0.048) (Figure 2).
To study factors associated ROP, a forward conditional logistic regression analysis was conducted. All variables that were significantly associated with ROP on bivariate analysis, including average glucose concentration, days on oxygen, days on respiratory support and variables in Table 2 were entered into the model. Only average blood glucose was significantly associated with ROP with odds ratio 1.77 (95% CI: 1.08 to 2.86), P=0.024. When analysis was repeated using maximum glucose concentration, results were not as significant: odds ratio 1.04 (95% CI: 1.003 to 1.084), P=0.036. Using ROC analysis, at a cutoff point>102.5 mg dl−1, average blood glucose concentration was associated with ROP, with a sensitivity of 84%, specificity of 80% and odds ratio of 21.9 (95% CI: 5.2 to 91.8), P<0.001. (Figure 3).
This is the first prospective study to test the association of hyperglycemia and ROP in premature infants. In our cohort, greater average blood glucose during the first week of life independently associated with the development of ROP.
Although the definition of hyperglycemia is controversial,3 high blood sugar is a common problem in premature infants, with studies showing incidence up to 58% to 80% in very low birth weight infants.35,36 Hyperglycemia in premature infants is related to developmentally immature hepatic glucose production, inadequate pancreatic beta cell response and insulin insensitivity.1,2 This can be accentuated by stress situations such as sepsis and intraventricular hemorrhage.3,37 Hyperglycemia can lead to glucosuria, osmotic diuresis and dehydration. Retrospectives studies have correlated hyperglycemia with increased mortality and morbidities, including longer hospital stay, adverse long-term outcome30,38, 39, 40, 41 and ROP.23, 24, 25, 26, 27
ROP is a vasoproliferative retinal disease that largely occurs in smaller and premature infants. Although in the past it was attributed to increased oxygen exposure,42 it is currently thought to be multifactorial.5 The role of hyperglycemia in the development of ROP can be explained by pathophysiological similarities between ROP and diabetic retinopathy.43 Similar to ROP, diabetic retinopathy is associated with proliferative vascular disease that can lead to retinal detachment.28 Hyperglycemia induces retinopathy by increased retinal blood flow and shear stresses.44,45 This effect is exaggerated if hyperglycemia is associated with hypoxemia,46,47 which is a common finding in premature infants leading to severe ROP.48 Reduction of glucose level has been associated with improvement in retinal blood flow in diabetic rats49 and prevention of proliferative retinopathy in diabetic adults.50 Additionally, hyperglycemia can stimulate production of vascular endothelial growth factor (VEGF) via activation of protein kinase C,51 with evidence of increased VEGF in retinal cells in multiple animal studies.52,53 VEGF is implicated in the genesis of both ROP and diabetic retinopathy and is the therapeutic target of clinical trials to prevent ROP.54,55 Moreover, insulin-like growth factor-1 deficiency could also be responsible for glucose instability and ROP. Insulin-like growth factor-1 is known to be reduced in premature infants, and low serum concentration was associated with ROP.7,56
This prospective study validates the results of previous retrospective studies associating hyperglycemia with ROP.23, 24, 25, 26, 27,31,57 In our study, it was the average blood glucose concentration that was more significantly associated with ROP. This agrees with the findings of Chavez et al.,26 who concluded that it is not the single events of glucose⩾150 g dl−1 but actually the time-weighted glucose concentration in the first 30 days of life that independently predicts ROP. Similarly, Mohamed et al.27 concluded that it is the duration of hyperglycemia rather than the severity that is associated with ROP. It is of interest that the cutoff point above which average blood glucose is significantly associated with development of ROP is 102.5 mg dl−1, a level identified by most practitioners as normal. Similarly, in previous studies, time-weighted glucose level in the first 30 days of ⩾118 mg dl−1 was a predictor of severe ROP.26 This finding raises the question whether we really know a good definition for hyperglycemia in premature infants. Likely a definition of hyperglycemia should include both a level and duration to have meaningful correlation with outcome.
In this study, patients who developed ROP had younger gestational age, less birth weight, were exposed to longer periods of increased amount of oxygen and respiratory support and had less average weight gain. They also had increased maternal age, increased incidence of maternal hypertension, premature rupture of membrane, respiratory distress syndrome, increased exposure to phototherapy and less exposure to breast milk. This agrees with previous studies that showed similar associations.7,8,12,58, 59, 60, 61, 62 However, none of these factors continued to be significant enough to stay in the regression model. This could be related to the study being not powered to look into each of these variables.
The question is how to apply our findings in clinical practice. Our study emphasizes that it is not a single high blood glucose that matters but rather the overall average exposure to higher glucose concentrations. Management of hyperglycemia need not address single or few high readings but should aim to maintain glucose in a reasonable range in the first week of life. In his study, we did not use insulin to treat higher concentrations of glucose. Previous studies could not associate the use of insulin with decreased incidence of ROP; indeed, they raised concerns over the safety of insulin use and possible relationship with increased mortality.63,64 Moreover, insulin use by itself was found to be a stronger predictor of ROP than hyperglycemia.31 We may suggest avoiding the use of the relatively aggressive insulin treatment until an evidence-based definition of hyperglycemia is devised and a clear clinical advantage of insulin use is validated. Finally, we conducted this study at a major referral tertiary care center. Infants recruited in this study were acutely ill, which constitutes a limitation in extrapolating the results to the general preterm population.
In a cohort of premature infants, elevated average blood glucose concentrations in the first week of life is associated with development of ROP. More research is needed to identify the target blood glucose concentrations and the means to maintain it without increasing risks of morbidity and mortality. Randomized trials that aim to shorten the duration of hyperglycemia, rather than decrease the peak values of glucose, during the first week of life and its relationship with ROP are needed. It will also be interesting to study the impact of strategies that stimulate endogenous insulin secretion, such as the early introduction of enteral feeds and the more aggressive supplementation of amino acids in parenteral solutions, and limiting lipid infusion to minimize gluconeogenesis.
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The authors declare no conflict of interest.
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Mohsen, L., Abou-Alam, M., El-Dib, M. et al. A prospective study on hyperglycemia and retinopathy of prematurity. J Perinatol 34, 453–457 (2014) doi:10.1038/jp.2014.49
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