A Prospective Study on Hyperglycemia and Retinopathy of Prematurity

ORIGINAL ARTICLE A prospective study on hyperglycemia and retinopathy of prematurity

L Mohsen1, M Abou-Alam1, M El-Dib2, M Labib1, M Elsada3 and H Aly2

OBJECTIVE: 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. STUDY DESIGN: Premature infants (o1500 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 readingo50 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. RESULT: 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. CONCLUSION: 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. Journal of Perinatology (2014) 34, 453–457; doi:10.1038/jp.2014.49; published online 27 March 2014

INTRODUCTION hyperalimentation,15,16 blood transfusions11,17 and vitamin E 18 Hyperglycemia is a significant risk factor for morbidity and deficiency. Moreover, ROP has been associated with the 19 mortality in preterm infants. There are multiple physiological presence of patent ductus arteriosus, bronchopulmonary and biochemical mechanisms in preterm infants that can lead to dysplasia,19 sepsis,16,20 systemic candidiasis21 and intraventricular excess glucose production, insulin resistance or glucose intoler- hemorrhage.22 ance; the sequelae of these disturbances in glucose metabolism Several retrospective studies have recently suggested hyper- – are extensive.1,2 Hyperglycemia could be associated with osmotic glycemia as a possible risk factor for ROP.23 27 Hyperglycemia is diuresis and dehydration, which increase the risk of cerebral commonly associated with many conditions in very low birth bleeding and electrolyte imbalance. There are also concerns that it weight infant, including sepsis, candidiasis, intraventricular may be associated with increased mortality and other morbidities, hemorrhage and postnatal steroids, all of which are frequently such as decreased immunity, increased infection, poor wound encountered in infants who later develop ROP.23 Meanwhile, it is healing and loss of skeletal and cardiac muscles.3,4 quite plausible that hyperglycemia imposes biological changes to Retinopathy of prematurity (ROP) remains a leading cause the retina; adults with poorly controlled diabetes develop a of morbidity in very low birth weight infants.5 The provision distinct neoproliferative retinopathy that is particularly identified of supplemental oxygen, while a major risk factor, is not the in patients with elevated serum glucose over prolonged periods.28 only cause of the disease as demonstrated by a series of low There has been a consensus agreement for the need to birth weight infants who developed ROP without ever receiving prospectively test the association of hyperglycemia with – any oxygen.6 Other proposed risks for the development of ROP ROP.29 31 To the best of our knowledge, we are not aware of include poor postnatal growth,7,8 hypoxia,9 hypercarbia,10 any prospective study to address such an association that is hypocarbia,11 exposure to prolonged and aggressive mechanical critically important, especially with the growing interest in early ventilation,12 inotrope therapy,6 postnatal steroids,13,14 prolonged and aggressive parenteral nutrition. The aim of this prospective

1Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt; 2Department of Neonatology, The George Washington University and Children’s National Medical Center, Washington, DC, USA and 3Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt. Correspondence: Dr H Aly, Newborn Services, The George Washington University Hospital, 900 23rd Street, NW, Suite G-2092, Room G-132, Washington, DC 20037, USA. E-mail: [email protected] Received 25 November 2013; revised 14 February 2014; accepted 14 February 2014; published online 27 March 2014 Hyperglycemia and ROP L Mohsen et al 454 cohort study was to determine whether elevated glucose RESULTS concentration is an independent risk factor for the development The study was conducted on 65 preterm neonates admitted to the of ROP in premature infants. 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 METHODS weight or mode of delivery. Infants in the hyperglycemia group Patients were more likely to be females, had greater acuity of illness using We conducted a prospective cohort study on premature neonates the Clinical Risk Index for Babies Score, with medians (ranges) of admitted to the neonatal intensive care unit (NICU) at Cairo University 1 (0 to 6) vs 2 (0 to 7), P = 0.001, and received more frequent red Children’s Hospital, which is the largest referral tertiary care unit in the cell transfusions (Table 1). In the hyperglycemia group, there was country. Infants were included in the study if admitted within 24 h of life no significant difference between the mean bedside glucose vs − with gestational age (GA) ⩽ 32 weeks or birth weighto1500 g. Infants with serum laboratory testing; 267.6 ± 101.2 vs 250 ± 86.4 mg dl 1, major congenital anomalies were excluded from the study. The study was P = 0.46. approved by the ethics committee and was conducted in accordance with Forty-six infants (70.8%) had normal fundus examination, the University bylaws for human research. Parental consents were while 19 cases (29.2%) had ROP. Out of the 19 ROP cases, 13 obtained for all subjects. had stage-1, 4 infants had stage-2, and 2 infants had stage-3. Full maternal and perinatal history was collected for all the studied Compared with non-ROP infants (n = 46), cases with ROP (n = 19) neonates. Other NICU data such as the use of oxygen, ventilation and fi o phototherapy were documented. Data on date of start and day of full were signi cantly of younger gestational age (P 0.001), smaller establishment of enteral feeds, type of feeding and full caloric intake were birth weight (Po0.001), more likely to have respiratory distress recorded. (P = 0.001) and exposed to phototherapy (P = 0.007). Maternal and neonatal factors associated with ROP are presented in Table 2. Eye examination There were more cases of ROP in the hyperglycemia group Fundus examination was initially done at 4 to 6 weeks in compliance 32 compared with the euglycemia group (45% vs 15%, P = 0.007), with the recommendations of American Academy of Pediatrics. odds ratio 4.776 (95% confidence interval (CI): 1.46 to 15.60). Follow-up examinations were scheduled during the NICU stay and after fi Figure 1 presents average daily glucose concentrations in infants hospital discharge as based on retinal ndings. Examinations were fi performed by experienced pediatric ophthalmologists while masked with and without ROP during the rst week of life. Mean, to the glycemia condition of the infants. Retinal examination was maximum and minimum values for glucose concentrations in done using binocular indirect ophthalmoscope, lid speculum and scleral ROP and non-ROP infants are shown in Table 3. Infants with ROP depressors. Before examination, proper dilation of the pupil was performed had significantly higher average and maximum glucose values. using a topical anesthetic followed by an eye drop combination Hypoglycemia was detected in 13 (20%) of the studied population. (0.2% cyclopentolate and 1% phenylephrine). Stages of severity and the The incidence of ROP in infants with hypoglycemia was 15%, zones for the extent of ROP were categorized by the lowest zone whereas ROP in non-hypoglycemic patients was 33%; this differ- and the highest stage observed in each eye using the international ence was not significant (P = 0.315). classification of ROP.33,34 Duration of respiratory support (continuous positive airway pressure or mechanical ventilation), duration of oxygen therapy Glucose measurement and the concentration of the administered oxygen (FiO2)duringthe Routine laboratory investigations were obtained from all cases, including first 3 days were all significantly higher in ROP cases (Table 4). complete blood picture, blood chemistry and blood gases. In addition, Compared with non-ROP infants, infants who developed ROP had glucose concentration was checked using point-of-care glucometer delayed onset to introduce enteral feeds (7.6 ± 4.5 vs 5 ± 3.4 days, (Optuim Xceed, Abbott, lake Forest, IL, USA). Glucose concentration was P = 0.01), to reach full enteral feed (25.1 ± 6.3 vs 20.2 ± 7.8 days, then measured on admission every 8 h daily for 7 days. For any glucose P = 0.008) and gained less weight (P = 0.048) (Figure 2). readingo50 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 Table 1. Demographic and clinical characteristics of the study all the subjects by decreasing glucose infusion. None of the study = infants received insulin. Hypoglycemia was defined as blood glucose population (n 65) o50 mg dl − 1. Characteristics Euglycemia Hyperglycemia P-value group (n = 34) group (n = 31) Statistical analysis Gestational age (weeks) 31.2 ± 1 30.9 ± 1.4 0.23 Data were coded and double entry was done to check validity. Data were Birth weight (g) 1446 ± 193 1318 ± 242 0.021 analyzed using the SPSS (Statistical Package for the Social Science, Sex (% of male) 19 (56) 8 (26) 0.023 Chicago, IL, USA) version 18. Data were summarized using mean, s.d. and Cesarean section 24 (71) 24 (77) 0.58 range for continuous variables and percentage for categorical variables. Chorioamnionitis 0 2 (7) 0.22 Comparisons between groups were done using t-test for continuous Maternal hypertension 3 (9) 6 (19) 0.22 variables and chi-squared test for categorical variables. Logistic regression Phototherapy 17 (50) 14 (45) 0.7 model was used to test the association of hyperglycemia and ROP while Use of breast milk 22 (65) 13 (42) 0.07 controlling for confounding variables. P-valueso0.05 were considered as fi Bronchopulmonary 4 (12) 5 (16) 0.44 statistically signi cant. dysplasia Intraventricular 5 (15) 7 (23) 0.31 Sample size hemorrhage Retinopathy of 5 (15) 14 (45) 0.007 Previous studies showed a 40% to 50% difference in ROP in hyperglycemic 24,29 prematurity vs euglycemic patients. With the presumption of a 30% difference in Death 0 4 (13) 0.031 ROP between hyperglycemia and euglycemia, and an estimated incidence of hyperglycemia in 50% of preterm infants in our study, a sample size Data are presented as number (%), except for gestational age and birth of 60 would be adequate to detect such difference (power = 80% and weight where they are presented as mean ± s.d. α = 0.05).

Table 2. Maternal and neonatal factors associated with ROP Table 4. Respiratory management of ROP and non-ROP patients

Risk factor ROP (n = 19) Non-ROP P-value Management ROP Non-ROP P-value (n = 46) Days on mechanical 10.5 ± 7.7 8.8 ± 14.8 0.023 Maternal age (years) 30.3 ± 3.1 28.7 ± 2.4 0.045 ventilation or CPAP Maternal hypertension 7 (37) 2 (4) 0.002 FiO2 on DOL 1 0.52 ± 0.09 0.44 ± 0.14 0.016 Premature rupture of 7 (37) 6 (9) 0.036 FiO2 on DOL 2 0.52 ± 0.09 0.39 ± 0.17 0.003 membranes FiO2 on DOL 3 0.55 ± 0.13 0.39 ± 0.16 o0.001 Gestational age (weeks) 30 ± 1 31.5 ± 0.9 o0.001 Oxygen days 26.9 ± 10.1 18.6 ± 18 0.001 Birth weight (g) 1227 ± 204 1450 ± 202 o0.001 Respiratory distress 17 (89) 21 (46) 0.001 Abbreviations: CPAP, continuous positive airway pressure; DOL, day of life; Phototherapy 14 (73) 17 (37) 0.007 ROP, retinopathy of prematurity. ± Use of breast milk 1 (5) 13 (28) 0.04 Data are presented as mean s.d. Abbreviation: ROP, retinopathy of prematurity. Data are presented as number (%), except for maternal age, gestational age and birth weight where they are presented as mean ± s.d. 25

* 140

120 Average weight gain (g)

5 ROP Non-ROP 100 Figure 2. Average daily weight gain in retinopathy of prematurity (ROP) and non-ROP patients. *P = 0.048, t-test was used. Average glucose (mg/dl)

80 D1 D2 D3 D4 D5 D6 D7 Day of life Figure 1. Glucose concentrations in the study population during the ﬁrst week of life. Solid line represents retinopathy of prematurity (ROP) patients and dotted line represents non-ROP patients. Data are expressed in mean and s.e.m. (mg dl − 1).

Table 3. Relationship between glucose concentrations and ROP

Test ROP Non-ROP P-value

Maximum bedside glucose 280 ± 117 161 ± 63 o0.001 concentration Average bedside glucose 119 ± 19 97 ± 10 o0.001 Minimum bedside glucose 59 ± 14 56 ± 16 0.42 Average high serum glucosea 311 ± 80 194 ± 59 o0.001 Average low serum glucoseb 49 ± 445± 8 0.3 Figure 3. Receiver operating characteristic curve for the association Abbreviation: ROP, retinopathy of prematurity. between average blood glucose and retinopathy of prematu- Data are presented as mean ± s.d. (mg dlÀ1) o − rity. Area under the curve: 0.893, P 0.001; at a cutoff value of aDone when the bedside concentration was>150 mg dl 1. 102.5 mg dl − 1, sensitivity = 84% and speciﬁcity = 80%. bDone when the bedside concentration waso50 mg dl − 1.

To study factors associated ROP, a forward conditional logistic P = 0.036. Using ROC analysis, at a cutoff point>102.5 mg dl − 1, regression analysis was conducted. All variables that were average blood glucose concentration was associated with ROP, significantly associated with ROP on bivariate analysis, including with a sensitivity of 84%, specificity of 80% and odds ratio of 21.9 average glucose concentration, days on oxygen, days on respira- (95% CI: 5.2 to 91.8), Po0.001. (Figure 3). tory 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 DISCUSSION was repeated using maximum glucose concentration, results This is the first prospective study to test the association of were not as significant: odds ratio 1.04 (95% CI: 1.003 to 1.084), hyperglycemia and ROP in premature infants. In our cohort,

© 2014 Nature America, Inc. Journal of Perinatology (2014), 453 – 457 Hyperglycemia and ROP L Mohsen et al 456 greater average blood glucose during the first week of life The question is how to apply our findings in clinical practice. Our independently associated with the development of ROP. study emphasizes that it is not a single high blood glucose that Although the definition of hyperglycemia is controversial,3 matters but rather the overall average exposure to higher glucose high blood sugar is a common problem in premature infants, concentrations. Management of hyperglycemia need not address with studies showing incidence up to 58% to 80% in very low birth single or few high readings but should aim to maintain glucose in weight infants.35,36 Hyperglycemia in premature infants is related a reasonable range in the first week of life. In his study, we did not to developmentally immature hepatic glucose production, inade- use insulin to treat higher concentrations of glucose. Previous quate pancreatic beta cell response and insulin insensitivity.1,2 studies could not associate the use of insulin with decreased This can be accentuated by stress situations such as sepsis incidence of ROP; indeed, they raised concerns over the safety of and intraventricular hemorrhage.3,37 Hyperglycemia can lead to insulin use and possible relationship with increased mortality.63,64 glucosuria, osmotic diuresis and dehydration. Retrospectives Moreover, insulin use by itself was found to be a stronger studies have correlated hyperglycemia with increased mortality predictor of ROP than hyperglycemia.31 We may suggest avoiding and morbidities, including longer hospital stay, adverse long-term the use of the relatively aggressive insulin treatment until an outcome30,38–41 and ROP.23–27 evidence-based definition of hyperglycemia is devised and a clear ROP is a vasoproliferative retinal disease that largely occurs clinical advantage of insulin use is validated. Finally, we conducted in smaller and premature infants. Although in the past it was this study at a major referral tertiary care center. Infants recruited attributed to increased oxygen exposure,42 it is currently thought in this study were acutely ill, which constitutes a limitation in to be multifactorial.5 The role of hyperglycemia in the develop- extrapolating the results to the general preterm population. ment 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 CONCLUSION 28 can lead to retinal detachment. Hyperglycemia induces retino- In a cohort of premature infants, elevated average blood glucose fl 44,45 pathy by increased retinal blood ow and shear stresses. This concentrations in the first week of life is associated with effect is exaggerated if hyperglycemia is associated with development of ROP. More research is needed to identify the hypoxemia,46,47 which is a common finding in premature infants 48 target blood glucose concentrations and the means to maintain it leading to severe ROP. Reduction of glucose level has been without increasing risks of morbidity and mortality. Randomized associated with improvement in retinal blood flow in diabetic 49 trials that aim to shorten the duration of hyperglycemia, rather rats and prevention of proliferative retinopathy in diabetic fi 50 than decrease the peak values of glucose, during the rst week adults. Additionally, hyperglycemia can stimulate production of of life and its relationship with ROP are needed. It will also be vascular endothelial growth factor (VEGF) via activation of protein interesting to study the impact of strategies that stimulate kinase C,51 with evidence of increased VEGF in retinal cells in 52,53 endogenous insulin secretion, such as the early introduction of multiple animal studies. VEGF is implicated in the genesis of enteral feeds and the more aggressive supplementation of amino both ROP and diabetic retinopathy and is the therapeutic target of 54,55 acids in parenteral solutions, and limiting lipid infusion to clinical trials to prevent ROP. Moreover, insulin-like growth minimize gluconeogenesis. 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 CONFLICT OF INTEREST with ROP.7,56 fl This prospective study validates the results of previous retro- The authors declare no con ict of interest. spective studies associating hyperglycemia with ROP.23–27,31,57 In our study, it was the average blood glucose concentration that REFERENCES was more significantly associated with ROP. This agrees with the findings of Chavez et al.,26 who concluded that it is not the single 1 Cowett RM, Rapoza RE, Gelardi NL. 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