Incidence of Retinopathy of Prematurity and Risk Factors Among Premature Infants at a Neonatal Intensive Care Unit in Canada

Gloria Isaza, MD; Sourabh Arora, MD; Manpartap Bal, MD; Varun Chaudhary, FRCSC, MD

ABSTRACT
Purpose: To study the incidence of retinopathy of prematurity (ROP) in a neonatal intensive care unit and obtain information on risk factors associated with ROP. Methods: Four hundred twenty-three infants were screened for ROP between July 2006 and July 2010. Demographic information, clinical data, and risk factors were reviewed. Results: The incidence was 40.4% (171 infants) for ROP, 9.2% (39 infants) for severe ROP, and 5.67% (24 infants) for laser treatment. Mean gestational age and birth weight were signicantly lower among infants with ROP versus those without ROP (26 0.13 vs 28.55 0.12 weeks, P < .0001 and 840.5 17.49 vs 1,190.24 20.20 g, P < .0001, respectively). Birth weight (P < .001), gestational age (P < .001), mechanical ventilation therapy (P = .039), and necrotizing enterocolitis (P = .019) were independent risk factors for ROP. Conclusion: Gestational age and birth weight were the most signicant risk factors for developing ROP. The study population had an elevated percentage of infants with birth weight less than 1,000 g (extremely low birth weight), yet there was no corresponding increase in severe ROP incidence and treatment when compared to other studies. [J Pediatr Ophthalmol Strabismus 2013;50:27-32.]

INTRODUCTION Retinopathy of prematurity (ROP) is a leading cause of blindness affecting approximately 50,000 children worldwide.1,2 The disease is caused by abnormal vascular proliferation of the developing retina and increasing evidence supports that it is a multifactorial disease. Although most cases regress, ROP may progress to severe ROP, which is associated with an increased risk of blindness due to retinal detachment. Other complications may include macular folds, refractive amblyopia, and strabismic amblyopia.3-7 Early detection of severe ROP and assessing risk fac-

tors allow specic treatment intervention to be implemented, decreasing the severity of ROP sequelae and reducing unfavorable outcomes.8 Reports about the incidence of ROP vary; it may be increasing because of increased survival of extremely preterm infants.9,10 On the other hand, some studies have reported that advances in neonatal care have decreased the overall incidence of ROP.11,12 Studies have also documented many associated risk factors for ROP, such as gestational age, birth weight, oxygen supplementation, intraventricular hemorrhage, sepsis, and blood transfusion.13-22

From the Department of Surgery (GI, VC), Division of Ophthalmology, McMaster University, Hamilton, Ontario; the Department of Ophthalmology (MB), University of Ottawa, Ottawa, Ontario; and the Department of Ophthalmology (SA), University of Alberta, Edmonton, Alberta, Canada. Originally submitted June 8, 2012. Accepted for publication August 22, 2012. Posted online December 4, 2012. The authors have no nancial or proprietary interest in the materials presented herein. Address correspondence to Gloria Isaza, MD, McMaster University Medical Centre, 4V2 Clinic, 1200 Main St. West, Hamilton, Ontario, L8N 3Z5 Canada. E-mail: isazazgm@mcmaster.ca doi: 10.3928/01913913-20121127-02

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The aim of the current retrospective study was to identify the incidence of ROP and the associated risk factors of ROP in the second largest Canadian neonatal intensive care unit from July 2006 to July 2010. We identied baseline characteristics, demographic information, and comorbidities, and analyzed the association with ROP by univariate and multivariate logistic regression models. PATIENTS AND METHODS The retrospective chart study was conducted at McMaster Hospital between July 2006 and July 2010. Data were extracted from The Canadian Neonatal Network, which is the national registry that maintains clinical information about neonates. Approval for this study was obtained from the Health Research Ethics Board. All infants admitted to the neonatal intensive care unit with a birth weight less than 1,500 g or gestational age less than 32 weeks were screened for ROP. Additional infants weighing more than 1,500 g, gestational age greater than 32 weeks, or both were screened, following a special request from the attending neonatologist based on an increased perceived risk. Infants born with gestational age of 27 weeks or less were rst examined at 31 weeks postmenstrual age. Beyond 27 weeks gestational age, the rst examination was performed 4 weeks after birth. The examination was performed under topical anesthesia using 0.5% proparacaine eye drops and supportive oral sucrose. Pupils were dilated using a topical administration of two drops of cyclopentolate 0.2% and phenylephrine 1% (Alcon Laboratories, Inc., Mississauga, Ontario) at 10-minute intervals. Indirect ophthalmoscopy was performed using a binocular indirect ophthalmoscope and 28 diopter lens. An infant speculum and scleral depressor were also used to perform the examination. ROP status was documented using the International Classication of ROP, including stage, zone, and extent of disease and presence or absence of plus disease.23,24 Infants with ROP were routinely examined every 1 to 2 weeks, but some infants were examined as frequently as twice per week or as infrequently as once every 3 weeks depending on the zone and severity of ROP.25 Interobserver variation of examination results is minimal because more than 90% of screening examinations during this time period were performed by a single physician (GI). Infants requiring laser photocoagulation treatment were transferred to another
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hospital for the procedure and most were readmitted to our hospital following treatment. Treatment was determined following the Early Treatment for Retinopathy of Prematurity Study criteria.8,26 For analysis, the highest stage or most severe ROP in either eye for an individual infant was recorded. Severe ROP was dened in this study as stage 3 ROP or worse. Infants were placed in one of ve gestational age and birth weight groups for purposes of comparison. These groups were assigned based on the results of other studies for ease of comparison, and to provide an even distribution of data obtained in this study. Risk factors such as gestational age, birth weight, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, oxygen therapy, perinatal infection, blood transfusion, and gender were extracted from the database for comparison of screened infants who had ROP and those who did not. Oxygen therapy protocols were dened by the neonatal intensive care unit. For infants of 32 weeks gestational age or less, the high saturation limit on oxygen is 93% and the low saturation limit is 84%. On room air, the high saturation limit on oxygen is 100% and the low saturation limit is 84%. For infants of 33 to 37 weeks gestational age, the saturation limits on oxygen range from 88% to 95%. On room air, the high saturation limit on oxygen is 100% and the low saturation limit is 88%. These parameters have been employed in the unit to limit oxygens inuence as a risk factor for the development of ROP. Statistical analysis was performed using SPSS software (version 17.0; SPSS, Inc., Chicago, IL). To assess the statistical signicance of gestational age groups as predictors for the incidence of ROP, a univariate analysis was conducted with the reference group being gestational age of 31 weeks or greater. The same process was completed for establishing a relationship between birth weight groups and incidence of ROP, with the reference group being birth weight of 1,500 g or greater. To assess other potential risk factors for developing ROP, such as gender, oxygen therapy, perinatal infection, transfusions, intraventricular hemorrhage, patent ductus arteriosus, and necrotizing enterocolitis, univariate analysis was conducted, with evaluation of odds ratios and condence intervals. To control all of these variables and estimate the independent risk factors for incidence of ROP, the previously mentioned risk factors were entered into a logistic regression multivariate analysis. P values, odd ratios, and condence intervals were extracted for all nine variables of interest.
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TABLE 1

Stages of ROP by Gestational Age

Gestational Age (wk) 24 25 to 26 27 to 28 29 to 30 31 Total
ROP = retinopathy of prematurity.

Non-ROP (%) 2 (5%) 24 (24%) 111 (70%) 76 (86%) 39 (97%) 252

Stage 1 (%) 5 (14%) 10 (10%) 16 (10%) 7 (8%) 0 38

Stage 2 (%) 19 (51%) 43 (43%) 26 (17%) 5 (6%) 1 (3%) 94

Stage 3 (%) 11 (30%) 22 (22%) 5 (3%) 0 0 38

Stage 4 (%) 0 1 (1%) 0 0 0 1

Total 37 100 158 88 40 423

TABLE 2

Stages of ROP by Birth Weight

Birth Weight (g) 750 751 to 1,000 1,001 to 1,250 1,251 to 1,500 1,500 Total Non-ROP 12 (14%) 64 (50%) 84 (78%) 51 (92%) 41 (91%) 252 Stage 1 (%) 10 (12%) 14 (10%) 11 (10%) 2 (4%) 1 (2%) 38 Stage 2 (%) 38 (44%) 41 (32%) 10 (9%) 2 (4%) 3 (7%) 94 Stage 3 (%) 25 (29%) 10 (8%) 3 (3%) 0 0 38 Stage 4 (%) 1 (1%) 0 0 0 0 1 Total 86 129 108 55 45 423

ROP = retinopathy of prematurity.

RESULTS From July 2006 to July 2010, there were 503 infants eligible for ROP screening in the neonatal intensive care unit. Fifteen infants were discharged prior to inpatient eye screening. Sixty-ve infants were excluded due to incomplete eye examination data as a result of the infant not surviving to the time of screening. Therefore, during the study period, 423 infants fullled the inclusion criteria, having complete clinical data, and were included in this analysis. Among the entire group of 503 infants, 113 (23%) were born in Hamilton and the rest (77%) were referred from other regions (Niagara 20%, Waterloo 18%, Grand River 13%, Halton 11%, Wellington 6%, Greater Toronto Area 4%, and other regions 5%). Fifty-seven percent of the infants were male. For the entire cohort, the overall incidence of any ROP was 40.4% (171 of 423 infants). The mean gestational age was 27.5 weeks (range: 23 to 36 weeks) at birth, 26 weeks (range: 23 to 31 weeks) for infants with ROP , 25.2 weeks (range: 23 to 28 weeks) for infants with severe ROP, and 28.5 weeks (range: 24 to 36 weeks) for infants without ROP. All 171 infants with

ROP had a gestational age of 31 weeks or less. Table 1 displays the stages of ROP by gestational age. The mean overall birth weight was 1,054 g (range: 470 to 2,460 g). The mean birth weight in infants with ROP was 840 g (range: 500 to 1,890 g), which was signicantly lower than in the infants without ROP, whose mean birth weight was 1,191 g (range: 470 to 2,460 g) (P < .001). Two hundred fourteen infants (50.5%) were classied as having extremely low birth weight (ELBW [dened as birth weight less than 1,000 g]), of whom 138 (64.4%) had ROP. Eighty-ve infants (20%) had birth weight of 750 g or less, of whom 85.8% had ROP. ROP was present in no infants with birth weight of 1,890 g or greater and in only 0.59% of infants with birth weight greater than 1,500 g. Of the infants who had ROP, 80% (137 of 171 infants) had a birth weight of 1,000 g or less. The mean birth weight in infants with severe ROP was 730.3 g (range: 500 to 1,095 g). Table 2 displays the stages of ROP by birth weight. The overall incidence of severe ROP was 9.2% (39 infants). The overall incidence of laser treatment was 5.67% (24 infants). All infants were sent to other hospitals for laser treatment. Only one infant
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TABLE 3

Univariate and Multivariate Determinants of ROP

Risk Factor Male gender GAa BW
a

ROP Positive 148 25.99 (mean) 841 (mean) 33.1 (mean) 82/171 137/171 90/171 77/171 14/171

ROP Negative 95 28.61 (mean) 1,198 (mean) 9.7 (mean) 83/252 125/252 84/252 73/252 4/252

Unadjusted OR 0.89 (0.52 to 1.51) 5.10 (3.68 to 7.04) 3.56 (2.74 to 4.63) 2.75 (2.11 to 3.58) 1.88 (1.26 to 2.80) 4.09 (2.61 to 6.42) 2.22 (1.49 to 3.31) 2.01 (1.34 to 3.01) 5.95 (1.80 to 17.21)

Adjusted OR 0.86 (0.58 to 1.27) 2.64 (1.73 to 4.03) 1.90 (1.34 to 2.69) 1.37 (1.01 to 1.86) 1.21 (0.69 to 2.14) 0.70 (0.36 to 1.36) 1.39 (0.80 to 2.40) 1.31 (0.76 to 2.24) 9.01 (2.06 to 43.47)

Days on ventilation therapya Perinatal infection Transfusions IVH PDA NECa

ROP = retinopathy of prematurity; OR = odds ratio; GA = gestational age; BW = birth weight; IVH = intraventricular hemorrhage; PDA = patent ductus arteriosus; NEC = necrotizing enterocolitis. a Variables achieved significance (P < .05) on multivariate analysis and thus represent independent risk factors for ROP.

developed stage 4 ROP and none developed stage 5 ROP during the study period. Three hundred fty-one infants underwent mechanical ventilation therapy at least once during their stay at the neonatal intensive care unit, 165 infants had perinatal infection, 262 infants received transfusion of any blood product, 174 had intraventricular hemorrhage, 150 had patent ductus arteriosus, and 18 had necrotizing enterocolitis. Perinatal risk factors for ROP are summarized in Table 3. Multivariate analysis showed that gestational age, birth weight, presence of necrotizing enterocolitis, and number of days on mechanical ventilation therapy were independently associated with ROP in order of signicance based on P values. This logistic regression demonstrated that the most signicant adjusted risk factors for ROP were gestational age (odds ratio: 2.64, 95% condence interval; 1.73 to 4.03) and birth weight (odds ratio: 1.90, 95% condence interval 1.34 to 2.69). DISCUSSION The incidence of ROP has varied considerably over time. There have been reports about decrease, no change, and increase in the ROP incidence.11,12,27,28-32 It has been difcult to compare results because data availability, screening criteria methods, ethnicity, geographical location, risk factors, survival rate, and neonatal standards of care vary between studies.1,32 The overall ROP incidence in the current study was 40.4%. The Cryotherapy for Retinopathy of
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Prematurity Study33 reported an ROP incidence of 65.8% in infants with birth weight less than 1,251 g; a similar ROP incidence of 68% was reported from the Early Treatment for Retinopathy of Prematurity Study26,34,35 in infants having a similar birth weight. Comparison of the Cryotherapy for Retinopathy of Prematurity and Early Treatment for Retinopathy of Prematurity data with our study is limited because our study was based on a small sample size. The high percentage of stages 1 and 2 in our study may indicate that more instances of earlier ROP stages were observed and documented and may explain the overall incidence found in this study. Other studies performed in developed countries in infants with birth weight less than 1,000 g have shown that the overall ROP incidence varies between 47.3% and 82.5% and severe ROP incidence varies between 21.6% and 43.3%. A study by Hoogerwerf et al.20 of infants with a birth weight less than 1,500 g reported an incidence of overall ROP of 23.3% and an incidence of severe ROP of 1.2%, both lower than the ndings of the current study. A possible explanation is the higher percentage of infants with ELBW found in our study compared to their study (50.5% vs 35%). In addition, the infants in our study had a lower mean gestational age (27.5 vs 29.4 weeks) and birth weight (1,054 vs 1,177 g), respectively. The study by Dhaliwal et al.36 of infants with a birth weight less than 1,500 g, found a lower overall ROP incidence compared to our study (17% vs 40.4%) but the incidence of severe ROP and treatCopyright SLACK Incorporated

ment were similar to our study (9% vs 8.5% and 5% vs 5.6%, respectively). Our study also had a higher percentage of infants with ELBW (50.5% vs 27.6%) and smaller and younger infants compared to their study: mean gestational age (27.6 vs 29 weeks) and mean birth weight (1,054 g vs 1,240 g). Gilbert et al.37 compared gestational age and birth weight between countries with low, moderate, and high levels of development. In highly developed countries, they found that all infants with severe ROP had a mean gestational age less than 26 weeks and a mean birth weight less than 800 g, similar to the mean gestational age and birth weight found in infants with severe ROP in our study (25 weeks and 730 g, respectively). Our study showed a signicant relation between gestational age and birth weight with ROP. Birth weight and gestational age in the ROP group were signicantly lower than in the non-ROP group. This is consistent with other studies where birth weight and gestational age have been widely reported as important factors associated with ROP. In the literature there have been numerous investigators who studied the perinatal comorbidity risk factors, beyond birth weight and gestational age, that predispose to or inuence the development of ROP. These factors may contribute to ROP independently or produce an effect by interrelated or additive means. Our sample size did not allow for analysis of additive risk factors, but did nd that gestational age, birth weight, presence of necrotizing enterocolitis, and the number of days on mechanical ventilation therapy were independently associated with the development of any ROP. Mechanical ventilation delivers oxygen into the lungs at a positive pressure and a longer exposure to high oxygen pressure may contribute to ROP development. Shah et al. also determined that mechanical ventilation could be a risk factor for ROP.38 Recently, Giannantonio et al. published their ndings of ROP risk factors and noted that prolonged mechanical ventilation was also associated with ROP requiring treatment.39 Interestingly, Fortes Filho et al. found mechanical ventilation to be a signicant risk factor only for the development of any ROP in infants with a gestational age of 32 weeks or greater.40 They concluded that although infants with a lower gestational age are challenged with consequences of general immaturity, larger infants with higher gestational age tend to be sicker with more comorbidities. Necrotizing enterocolitis has been considered

as a possible risk factor in other studies of ROP development. Kumar et al. found that necrotizing enterocolitis was a signicant risk factor for severe ROP on univariate analysis.41 Giapros et al. found necrotizing enterocolitis in 8.3% of infants with any ROP and 4.5% in their study of 247 infants with gestational age less than 33 weeks and birth weight less than 1,501 g.42 We found a similar number of patients with necrotizing enterocolitis who had any ROP (8.2%), but our non-ROP group only had 1.6% infants with necrotizing enterocolitis. We acknowledge the limitations of our study. First, the study was conducted among inpatients at a neonatal intensive care unit and thus could misrepresent the general incidence of ROP. Second, our infants were referred to other hospitals when laser photocoagulation therapy was indicated and, although most infants came back to our hospital for follow-up, we were unable to access complete follow-up data for transferred patients, which may have resulted in a possible overestimation or underestimation of the true incidence of laser therapy and retina surgery. Given that 13% (65 of 503 patients) of our original population were excluded as a result of not surviving to the time of screening, the true incidence of ROP could be higher. Furthermore, our screening criteria were more inclusive than the recent American Academy of Pediatrics recommendation for screening at gestational age less than 30 weeks and birth weight less than 1,500 g. This may have also underestimated our incidence of ROP by increasing the number of unaffected patients. The current retrospective study of 423 infants represents one of the few studies of incidence and associated risk factors of ROP performed at a Canadian tertiary care center. Our results conrm the inuence of extreme prematurity, low gestational age, and birth weight on the incidence of ROP. Although our study had a high percentage of infants with ELBW, born most prematurely, we did not nd an associated increase in the incidence of severe ROP and treatment. We believe that a better understanding of ROP pathogenesis and the development of site-specic strategies for the treatment of premature infants and associated clinical conditions may decrease the incidence of severe ROP and the need for treatment. REFERENCES
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