- Email: [email protected]
Retinopathy of prematurity in southern Taiwan: A 10-year tertiary medical center study
+
MODEL
Journal of the Formosan Medical Association (2012) xx, 1e9
Available online at www.sciencedirect.com
journal homepage: www.jfma-online.com
ORIGINAL ARTICLE
Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study Mei-Lun Li a, Sheng-Min Hsu a,b, Yi-Sheng Chang a,b, Min-Hsiu Shih a, Yung-Chieh Lin c, Chyi-Her Lin c, Hui-Ju Tsai d, Sung-Huei Tseng a,* a
Department of Ophthalmology, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan c Department of Pediatrics, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan d Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan b
Received 13 January 2011; received in revised form 1 March 2012; accepted 6 March 2012
KEYWORDS refractive outcomes; retinopathy of prematurity; risk factors; treatment
Background/Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. This retrospective study investigated ROP, including incidence, demographic information,risk factors, treatments, and refractive outcomes, in southern Taiwan over a 10-year period. Methods: The authors retrieved the National Cheng Kung University Hospital database between the years 2000 and 2009 for newborns with a gestational age less than 32 weeks and/or with a birth weight less than 1500 g who had been screened for ROP. We recorded sex, birth weight, gestational age, in-hospital versus out-of-hospital birth, paternal and maternal ages, whether there were multiple gestations, parity, Apgar scores, length of hospital stay, risk factors, presence and severity of ROP and whether it was treated, and refraction at the last visit. Regression analyses were performed to identify risk factors for ROP. Results: A total of 503 live births were included. ROP was identified in 190 (37.8%) and met criteria for treatment in 59 (11.7%).ROP was diagnosed as stage 1, 2, 3, 4, and 5 in 61 (12.1%), 36 (7.2%), 81 (16.1%), 11 (2.2%), and 1 (0.2%) infant, respectively. Lower birth weight and younger gestational age were risk factors for greater severity of ROP (p < 0.001). Of the 167 with extremely low birth weight (<1000 g), 118 (70.7%) had ROP and 49 (29.3%) required treatment.On univariate analysis, low birth weight, younger gestational age, and risk factorssuch as respiratory distress syndrome, chronic lung disease, patent ductus arteriosus, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis were associated with ROP. Multivariate logistic regression
* Corresponding author. Department of Ophthalmology, National Cheng Kung University College of Medicine and Hospital, 138 Sheng-Li Rd, Tainan, Taiwan. E-mail address: [email protected] (S.-H. Tseng). 0929-6646/$ - see front matter Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. doi:10.1016/j.jfma.2012.03.002
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
2
M.-L. Li et al. analysis showed that only lower birth weight was a significant and independent risk factor for ROP. Myopia (76%)and anisometropia (28%)were common in advanced ROP. Conclusion: Low birth weight is a major risk factor for ROP. Infants with extremely low birth weight had a higher risk of severe ROP. Common ocular sequelae of advanced ROP were myopia and anisometropia. Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Introduction Premature infants are at risk of retinopathy of prematurity (ROP), characterized by abnormal vascular development of the retina.1 ROP may progress rapidly to an advanced stage in which malformation of eye structures leads to blindness as a result of retinal detachment, macular folds, and refractive or strabismic amblyopia.1e4 The International Classification of Retinopathy of Prematurity (ICROP) allows for comparison of the incidences and outcomes of this disease across populations.1,5 Previous large-scale studies such as the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)2,5,6 and Early Treatment of Retinopathy of Prematurity (ETROP)7 studies showed that early intervention is effective in preventing loss of visual acuity and adverse anatomic outcomes. Despite increased awareness of and improved treatments for ROP, however, this disease remains a leading cause of childhood blindness, accounting for up to 10% of cases in developed countries.8 A number of ROP studies have been conducted in Taiwan, reporting on the incidence,9e15 characteristics,9e11,13e17 treatment options,14,18 and visual outcomes of ROP. 14,19 Over the past decade, medical care for neonates in Taiwan has advanced greatly, as evidenced by the increased survival rate of low-birth-weight (BW) infants, including those with very low birth weight (VLBW) (<1500 g) and those with extremely low birth weight (ELBW) (<1000 g).9,20,21 As a result of these increased survival rates, ophthalmologists are to examine more infants for evaluation of ROP. We conducted the study to investigate the incidence, severity, treatment and treatment outcomes, and the risk factors for ROP among low BW infants at a tertiary medical center in southern Taiwan for the 10-year period from 2000 through 2009.
study protocol was approved by the institutional review board of National Cheng Kung University Hospital.
Retinopathy assessment ROP was staged using ICROP.1,5 The first ROP screening examination for infants born before 27 weeks GA was carried out at 31 to 33 weeks postmenstrual age and that for infants born between 27 and 32 weeks GA was undertaken at 4 weeks postnatal age. For this examination, both pupils were dilated by instillingone drop of 0.5% tropicamide and 0.5% phenylephrine three times until full dilation occurred. Indirect ophthalmoscopy was performed using a lid speculum and scleral indentation. The stage of ROP was not determined by just one single examination. Instead, the eyes were reexamined on a weekly or biweekly basis, depending on the fundus findings of the screening examination. Eyes without ROP were reexamined biweekly by retinal specialists (Drs Li, Hsu, and Chang) until full vascularization of the retina was achieved. Those with ROP were examined every week until regression occurred or until ROP reached the threshold for laser or cryotherapy treatment.7 The highest stage of ROP recorded was assigned to each infant. From 2000 until the end of 2007, eyes were treated if they met the ICROP classification1,5 for threshold disease, which is defined as stage 2 ROP with plus disease with 5 contiguous clock hours of disease or a total of 8 noncontiguous clock hours in zone 1 or 2.22 After 2007, eyes were treated if they had type 1 ROP according to the ETROP criteria,7 in which type 1 ROP was defined as (1) any stage with plus disease in zone I, or (2) stage 3 ROP without plus disease in zone I, or (3) disease in zone II that was at stage 2 or 3 with plus disease. Eyes with threshold ROP or type 1 ROP were treated with indirect diode laser photocoagulation or cryotherapy under general anesthesia.
Methods Assessment of risk factors for ROP Case identification This is a retrospective study reviewing of medical records at National Cheng Kung University Hospital, a tertiary referral hospital in southern Taiwan, for all infants with either BW < 1500 g or gestational age (GA) < 32 weeks admitted between January 1, 2000, and December 31, 2009. We excluded those infants who failed to survive longer than 28 days for the first ROP screening, who did not live for 6 months postnatally to complete ROP screening, and who had congenital diseases such as chromosomal anomaly. The
In addition to BW and GA, we assessed the following for association with ROP: in-hospital or out-of-hospital birth, paternal age, maternal age, multiple gestations, parity, Apgar scores at 1 minute and 5 minutes, length of hospital stay, respiratory distress syndrome (RDS), mechanical ventilation, chronic lung disease (CLD), patent ductus arteriosus (PDA), prenatal maternal usage of steroid, postnatal surfactant use, postnatal indomethacin use, sepsis, intraventricular hemorrhage, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan
3
Refraction Cycloplegic refraction of the eyes was performed using a desktop computer autorefractometer (Topcon Corporation, Tokyo, Japan) after instilling onedrop of 0.5% tropicamide and 0.5% phenylephrine three times until the pupil dilated. Infants who were too small for desktop computer autorefractometry were assessed using retinoscopy. Refractive error values were converted to the spherical equivalent (SE).Myopia worse than -6.0 diopters (D) was considered to be advanced myopia. Anisometropia, or two eyes that have unequal power, greater than 1.5 D, was considered to be significant anisometropia. Refractive status was recorded at the age of the last ophthalmic visit.
Statistical analyses Statistical analyses were performed using the statistical package for social sciences software (SPSS 17.0 for Windows, SPSS Inc., Chicago, IL, USA) and Microsoft Excel software (Microsoft Corporation, Redmond, WA, USA). Descriptive statistics were expressed as mean 1 standard deviation. The chi-square test was used to compare categoric data related to clinical outcomes. Student t test and analysis of variance were used to compare continuous data. Univariate analyses were used to test for the potential risk
factors of ROP. If significant at p < 0.05, risk factors were included in the stepwise multivariable logistic regression analyses. The adjusted odds ratio and corresponding 95% confidence interval for the incidence of ROP was calculated for the risk factors in the model.
Results Patient characteristics Five hundred three infants (255 male and 248 female) met the criteria for inclusion in this study. Their BWs ranged from 455 to 1968 g (1157 313) and GA ranged from 21 to 38 weeks (29.1 2.7). ROP was identified in 190 infants (37.8%), and 59 infants (11.7%) underwent laser photocoagulation therapy or cryotherapy. Table 1 summarizes the characteristics of the 503 infants with or without ROP on the screening examination. There was a statistically significant difference in BW for infants with and without ROP (mean BW for those with ROP Z 940 251 g vs. 1288 272 g for those without ROP, p < 0.001). Of the 503 infants, 435 had very low BW (VLBW) (<1500 g), and 185 (42.5%) of the 435 had ROP. However, of the 167 with extremely low BW (ELBW) (<1000 g), 118 (70.7%) had ROP, compared with only 49 (29.3%) of those without ROP. As for the remaining 68 newborns weighing
Table 1 Characteristics of 503 premature infants with or without retinopathy of prematurity on initial screening, 2000-2009 (univariate analysis). Characteristic
Infants with ROP, n Z 190 (37.8%)
Infants without ROP, n Z 313 (62.2%)
p Value
Sex (% male)
101 (53.2)
154 (49.2)
Birth weight (g), number (%) <750 750-999 1000-1249 1250-1499 >1500 Mean (1 SD)
35 (18.4) 83 (43.7) 52 (27.4) 15 (7.9) 5 (2.6) 940 ( 251)
8 (2.6) 41 (13.1) 84 (26.8) 117 (37.4) 63 (20.1) 1288 ( 272)
<0.001
Gestational age (weeks), number (%) <26 26-28 29-31 32-38 Mean (1 SD )
52 (27.4) 99 (52.1) 28 (14.7) 11 (5.8) 27.0 (2.4)
4 (1.3) 64 (20.4) 173 (55.3) 72 (23.0) 30.1 (2.1)
<0.001
Out-of-hospital birth
33.5%
26.3%
0.106
Other characteristics, mean 1 SD Paternal age (years) Maternal age (years) Multiple gestation Parity (number) Apgar score, 1 minute Apgar score, 5 minutes Length of hospital stay (days)
34.1 5.6 31.5 5.0 2.3 1.4 1.7 0.8 4.7 2.0 6.9 1.8 66.2 39.8
33.4 6.0 29.9 5.3 2.1 1.8 1.6 0.7 5.6 2.0 7.8 1.7 45.1 33.5
0.406 0.006 0.330 0.064 <0.001 <0.001 <0.001
ROP Z retinopathy of prematurity; SD Z standard deviation.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
4
M.-L. Li et al.
>1500 g, only 5 (7.4%) screened positive for ROP and none of them required treatment. There was also a statistically significant difference in GA between infants with and those without ROP (GA 27.0 2.4 weeks for those with ROP vs. 30.1 2.1 weeks for those without ROP, p < 0.001). Additionally, ROP was more prevalent among infants born to older mothers, those with lower Apgar scores, and those with prolonged hospital stays (Table 1).
Correlation of stage of ROP with BW and GA As shown in Table 2, the stage of ROP correlated inversely with BW and GA. On average, infants with BWs < 900 g were more likely to develop threshold ROP or even more advanced stages that required treatment; however, there were a number of newborns weighing <900 g with ROP who did not reach the threshold level for treatment.Likewise, the mean BW of infants undergoing treatment for ROP was significantly lower than those with ROP not requiring treatment and lower than those without ROP (819 214 vs. 995 248 vs. 1288 272 g, p < 0.001)(Table 3). Fig. 1 shows the proportions of infants with treated ROP, untreated ROP, and no ROP, by BW. Among infants with VLBW and ELBW, 13.6 % and 29.3%, respectively, required treatment for ROP. A similar correlation was seen for GA, which was significantly lower for infants with ROP who required treatment compared with those with ROP not requiring treatment and those without ROP (26.4 2.7 vs. 27.4 2.5 vs. 30.2 2.7 weeks, p < 0.001) (Table 3). Overall, among infants with a GA < 32 weeks versus >32 weeks, ROP was diagnosed in 42.6% versus 13.3%, respectively. Fig. 2 shows the proportions of infants with treated ROP, untreated ROP, and no ROP, by GA. Among infants with GA < 26weeks, 26-28 weeks, 29-31 weeks, and > 32 weeks, treatment for ROP was required by 42.9%, 16.7%, 3.4%, and 1.2%, respectively. Only one infant in the >32-week GA group (GA Z 33 weeks) required treatment for ROP and this infant had a BW of 1120 g. After the treatment (retinal photocoagulation or cryotherapy), ROP regressed in 83.1% (n Z 49) of the treated infants. In the other 16.9% (n Z 10), ROP progressed to either stage 4 or 5 and required further surgical intervention.
Table 2
Refractive status of infants with ROP A total of 113 infants (55 male and 58 female) were brought back to the hospital for refractive examination. The mean age at this examination was 2.7 2.5 years (range, 0.2 to 9.7 years). Mean refractive error in these 113 infants was close to emmetropia (0.02 3.23 D), although the ranges were large (þ7.25 to -13.50 D). Of these 113 infants, 25 (50 eyes) had undergone treatment for ROP. Three of them progressed to stage 4 and the others regressed. As shown in Fig. 3, the 50 eyes that were treated for ROP had SEs of -3.50 4.27 D; 38 (76.0%) of these 50 eyes were myopic. Mean SEs in eyes with untreated ROP were 0.53 2.13 D,which were close to emmetropia,and eyes without ROP had mean SEs of 1.57 1.53 D. Advanced myopia (<-6.0 D) was noted in only 10 of 113 infants (8.4%), but in 17 eyes of 50 treated eyes (34.0%) (p < 0.001). Significant anisometropia (>1.5 D) was present in 12 of 113 infants (10.6%) and was found in a higher proportion of infants with treated ROP (n Z 7) compared with untreated ROP (n Z 5) or no ROP (n Z 0) (28.0%, 11.1%, and 0% respectively), and the differences were significant (pZ 0.004).
Risk factors for ROP On univariate analysis, patient characteristics associated with ROP were lower BW, younger GA, lower Apgar scores at 1 minute and 5 minutes, and longer length of hospital stay (Table 1). In addition, a significantly higher proportion of infants with ROP versus those without ROP had RDS, CLD, PDA, administration of surfactant or indomethacin, sepsis, upper gastrointestinal bleeding, blood transfusion, or necrotizing enterocolitis (Table 4). However, the stepwise multivariate logistic regression analysis showed that only low BW (adjusted odds ratio 0.996 [95% confidence interval 0.993-0.998]) was predictive of the development of ROP.
Discussion In our study, higher incidence of ROP has a significant association with lower BW, younger GA,lower Apgar scores at 1 minute and 5 minutes, longer length of hospital stay,
Maximum ROP stage on screening of 503 infants, by birth weight and gestational age.
Maximum ROP stage
Number (%)
Birth weight in grams, mean 1 SD (range)
Gestational age in weeks mean 1 SD (range)
None Stage 1 Stage 2 Stage 3 Subthreshold Threshold (3þ) Stage 4 Stage 5 Total patients
313 (62.2) 61 (12.1) 36 (7.2) 34 (6.8) 47 (9.3) 11 (2.2) 1 (0.2) 503 (100)
1288 272 (542-1968) 1030 238 (455-1716) 960 236 (472-1480) 969 274 (560-1760) 817 201 (460-1438) 841 275 (600-1484) 660 1157 313 (455-1968)
30 2.1 (23-36) 28 2.4 (24-38) 27 2.3 (24-35) 26 2.3 (21-30) 26 1.8 (23-32) 26 2.9 (24-33) 24 29.1 2.7 (21-38)
ROP Z retinopathy of prematurity; SD Z standard deviation.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan Table 3
5
Mean BW and GA in no ROP, untreated ROP, and treated ROP groups.
Mean BW 1 SD (g) Mean GA 1 SD (weeks)
No ROP, n Z 313 (62.2%)
Untreated ROP, n Z 131 (26.0%)
Treated ROP, n Z 59 (11.7%)
p Value
1288 272 30.2 2.7
995 248 27.4 2.5
819 214 26.4 2.7
<0.001 <0.001
BW Z birth weight; GA Z gestational age; ROP Z retinopathy of prematurity; SD Z standard deviation.
RDS, CLD, PDA, administration of surfactant or indomethacin, and sepsis, upper gastrointestinal bleeding, blood transfusion, or necrotizing enterocolitis on univariate analysis. However, on multivariate analysis, higher risk of ROP was predicted only by BW. Risk factors reported in the literature vary, in many cases attributable to differences in methodology, screening criteria, and indications for treatment of ROP. Regarding the relative predictive value of BW and GA, although GA is highly correlated with BW, a number of studies23,24 have previously reported that BW is a stronger predictor of ROP than GA. When compared with full-term infants, low BW infants are especially at increased risk of visual impairment.25 Two explanations for these findings have been given: (1) the high error rate when GA is estimated based on prenatal ultrasound results and (2) the possibility that premature infants with intrauterine growth retardation might be at higher risk of developing ROP because of their eventful clinical course, with conditions such as RDS, sepsis, upper gastrointestinal bleeding, necrotizing enterocolitis, and failure to thrive. Regarding variations in screening criteria, the Royal College of Pediatrics and Child Health (RCPCH)26 has recommended that infants with BW < 1501 g and/or GA < 32 weeks be screened for ROP, whereas the American Academy of Pediatrics has proposed screening for those with BW < 1500 g and/or GA < 28 weeks.22 The screening criteria we used in the study reported here are consistent with those of the RCPCH. Even so, one infant who, at a GA of 32 weeks and BW of 1760 g, did not meet RCPCH
Figure 1
guidelines for screening, developed stage 3 ROP in his right eye. He was not born in a neonatal center, had an older mother (37 years old), 1-minute Apgar score of 4, and received supplemental oxygen for the first 3 days of life. Although stage 3 ROP regressed spontaneously without treatment in this case, it reminds us that some infants with severe ROP might not meet current screening criteria. Regarding what additional factors might predict the need for screening, Fang et al.16 recommend that larger preterm infants should be screened for ROP if they have lower 1minute Apgar scores, oxygen supplementation more than 40% or for longer than 5 days, or an unstable clinical course. To these criteria, we would add, based on the study reported here, older maternal age, lower 5-minute as well as 1-minute Apgar scores,and oxygen supplementation as criteria for ROP screening. Regarding the relationship of ROP to BW and GA, ROP was diagnosed in 37.8% of 503 infants with GA < 32 weeks or BW < 1500 g. Among VLBW infants (<1500 g), the incidence of ROP was 42.5% and among ELBW infants (<1000 g) the incidence was 70.7%. Our overall incidence and incidence among VLBW infants are comparable to the 42.5% incidence of ROP reported in Taiwan between 1988 and 199127and a 36.5% incidence reported for the period 1996 to 2000.13 Among older premature infants (GA < 37 weeks), Wu et al.15 reported an incidence of ROP of just 13%. In the CRYO-ROP trial, the incidence of ROP was 65.8% among infants with BW < 1250 g and 81.6% in ELBW infants. Compared to this most widely cited CRYO-ROP study conducted in the mid-1980s, our results show
Rates of retinopathy of prematurity (ROP) stratified by birth weight (BW) and treatment.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
6
M.-L. Li et al.
Figure 2
Rates of retinopathy of prematurity (ROP) stratified by gestational age (GA) and treatment.
approximately 10% lower incidences of ROP for infantswith BW < 1250 g (56.1%) and ELBW (70.7%). Results similar to ours, however, were reported in a Taiwan study (36.5% incidence in infants <1600 g and 59.5 % incidence in ELBW infants).13 In studies conducted among western populations, incidences of ROP ranged between 15.7% and 48.9%,28e31 with a trend toward lower rates over time. This trend has been attributed to improvements in care for premature infants, such as surfactant prophylaxis to improve pulmonary maturity, continuous pulse oximetry, antenatal maternal steroids, and use oflower concentrations of oxygen.32e34 Without long-term longitudinal studies conducted among the same population using the same criteria, it is difficult for us to determine whether the incidence of ROP is changing in Taiwan. As the numbers of infants with ELBW and VLBW who survive increase,9,20,21,35,36 more infants are likely to require screening for ROP. Moreover, as improvements in care lead to survival of more ELBW infants without major neurologic or cognitive deficits,37 detection and treatment
10
Spherical equivalent (D)
5
0
-5
-10
-15
Treated ROP (n=25)
Untreated ROP (n=45)
No ROP (n=43)
Figure 3 Comparisons of refractive status among treated retinopathy of prematurity (ROP), untreated ROP, and no ROP groups. D Z diopter.
of ROP will be increasingly important to ensure optimal quality of life for these patients. In the study we report here, the incidence of treated ROP was 29.3% among ELBW infants. Incidences of ROP meeting treatment criteria in other recent domestic studies13e15 differ from ours depending on study criteria. Yang et at.14 reported an incidence of 13.5% for ROP requiring treatment between 1994 and 2003, whereas Liu et at.13 reported a lower incidence of ROP requiring treatment (8.2%) in premature infants weighing <1600 g. However, in a Beijing study,38 the incidence of treated ROP was 28.6% and 28.7% in a study of ELBW infants in the United States.24 Both findings are comparable to our results. Nonetheless, a study among Japanese infants found indications for treatment in up to 41%, which might be attributed to an 86.1% incidence of ROP for ELBW infants.39 However, only 17.0% of ELBW infants in a Brazil study were treated.31 Retinal neovascularization leads to retinal traction, retinal hemorrhage, and retinal detachment, finally affecting vision. In the past decade, the recommended treatment for type 1 and threshold ROP was peripheral ablation, and laser therapy was the preferred method of treatment rather than cryotherapy. However, the use of anti-vascular endothelial growth factor agents, primarily intravitreal bevacizumab, is currently an emerging treatment for type 1 and threshold ROP s.40 Off-label use of intravitreal bevacizumab therapy as monotherapy and in combination with conventional laser therapy or vitrectomy or both18 are current treatment options for type 1 and threshold ROP and the results seem promising. In our study, regression of retinal neovascularization was noted in 83.1% of the infants whose disease was treated. Our result is similar to that in the CRYO-ROP study,6 in which 74% of the eyes had a favorable outcome at 1 year, and almost the same as the 84% with a favorable outcome in the conventional treatment arm of the ETROP trial7 at 9 months. Our result is comparable as well to results in other published studies.6,7,40,41 Although laser therapy or cryotherapy effectively halts the progression of stage 3 to 4 ROP in most patients, these treatments actually destroy the peripheral retina and may lead to visual field defect and refractive changes. Therefore, the new treatment option, intravitreal bevacizumab therapy, may prevent visual field defect,
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan Table 4
7
Risk factors in newborns with or without retinopathy of prematurity (ROP) (univariate analysis).
Risk factors
Newborns without ROP, n Z 313
Newborns with ROP, n Z 190
p Value
Respiratory distress syndrome* Mechanical ventilation Chronic lung disease* Patent ductus arteriosus* Steroid exposure prenatally Surfactant usage* Indomethacin usage* Sepsis* Intraventricular hemorrhage Upper gastrointestinal bleeding* Blood transfusion* Necrotizing enterocolitis*
67.7% 86.9% 27.0% 39.6% 72.8% 26.9% 42.9% 41.6% 19.2% 16.0% 37.6% 15.7%
86.2% 84.2% 64.8% 58.5% 78.5% 53.1% 71.7% 61.2% 26.3% 34.6% 58.1% 26.1%
<0.001 0.57 <0.001 0.001 0.224 <0.001 <0.001 <0.001 0.113 <0.001 <0.001 0.006
*Statistically significant at the level of p < 0.05.
especially in zone I ROP patients,40 and decrease the possibility of progression to stage 4 or 5 after peripheral ablation, whereby functional visual outcomes are still not satisfying, even after vitrectomy or scleral buckling.42,43 Major concerns for premature infants, particularly those with ROP, are development of the eye, refractive status, and visual outcome. In the current study with an average follow-up of 2.7 years,the mean refractive errors of eyes without ROP, with untreated ROP, treated ROP were þ1.5 D, þ0.5 D, and -3.5 D, respectively.Approximately 75% of treated eyes in our study had myopia and approximately 25% hadadvanced myopia (<-6.0 D).Yang et al19 reported similar results in a recent domestic study: 77% of lasertreated eyes were myopic and 16.7% had worse than -6.0 D of myopia at an average patient age of 7 years. Rates of myopia may vary among studies because the incidence of myopia increases with increasing prematurity and severity of ROP.44e46 Myopia in infants with ROP is believed to be partly due to the disease process of ROP and partly a result of therapy for ROP. Factors accounting for this relationship include anomalies of corneal diameter and curvature, shorter anterior chamber, axial length, thicker lens, and laser effects on the sclera.6,44,47,48 A combination of various optical components results in complicated refractive outcomes. Another study found that lower BW and greater severity of ROP strongly predicted myopia and high myopia.25,47,49 Of note, Tasman50 reported that patients withROP and a high degree of myopia had a higher rate of retinal detachment in later life. This indication that ROP has lifelong consequences means that long-term follow-up is crucial for patients with treated ROP. The risk factors for ROP we identified in univariate analysis (RDS, CLD, PDA, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis) are in line with findings in other studies that ROP is associated with complex medical conditions that require prolonged treatment with oxygen.29,51,52 However, lower BW was the most important predictor of ROP. Our study has three major limitations. The first is its design, as a retrospective study with relatively small sample size compared with some other studies in the
literature.2,4,6,7,24,29,45,49 Ideally, a large, carefully designed population-based cohort study should be conducted of ROP throughout Taiwan. Second, the incidence of ROP in our study simply represented the clinical observations of premature infants at a single tertiary medical center and could not reflect the exact incidence of ROP in the area of southern Taiwan. Third, the refractive status in our study was examined at different ages among the study participants. This lack of a standardized age for final evaluation made it difficult to generalize and compare results among the study groups. An ideal study would measure refractive outcomes, optical components, and functional outcomes, such as visual acuity, at standardized ages over the long term, to assess the risk for amblyopia and other sequelae of ROP at various times/ages after treatment. In conclusion, our study confirmed the findings in previous studies that low BW significantly increases the risk for ROP. ELBW infants are at even higher risk of ROP and of more advanced ROP requiring immediate treatment compared with those with VLBW. Myopia and subsequent amblyopia and other ocular sequelae of ROP may cause lifelong problems.
Financial support None.
Acknowledgments The authors are grateful to Dr Sheng-Hsiang Lin and Ms Shang-Chi Lee of the Research Center for Clinical Medicine, National Cheng Kung University Hospital, for providing statistical analyses.
References 1. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130e4.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
8 2. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 1/2 years after randomization. Arch Ophthalmol 1996;114: 417e24. 3. Bremer DL, Palmer EA, Fellows RR, Baker JD, Hardy RJ, Tung B, et al. Strabismus in premature infants in the first year of life. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1998;116:329e33. 4. Quinn GE, Dobson V, Kivlin J, Kaufman LM, Repka MX, Reynolds JD, et al. Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1998;105:1292e300. 5. International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. Arch Ophthalmol 1987;105:906e12. 6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Status at 1 year. Arch Ophthalmol 1994;112: 903e12. 7. Early Treatment for Retinopathy of Prematurity Cooperative G. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121: 1684e94. 8. Steinkuller PG, Du L, Gilbert C, Foster A, Collins ML, Coats DK. Childhood blindness. J AAPOS 1999;3:26e32. 9. Lin HJ, Lin CC, Tsai SW, Lin HC, Su BH. Risk factors for retinopathy of prematurity in very low birth-weight infants. J Chin Med Assoc 2003;66:662e8. 10. Yang CM, Liu KR, Chen MS, Ko LS. Ocular fundus examination in premature infants. J Formos Med Assoc 1991;90:480e6. 11. Yang CS, Chen SJ, Lee FL, Hsu WM, Liu JH. Retinopathy of prematurity: screening, incidence and risk factors analysis. Zhonghua Yi Xue Za Zhi (Taipei) 2001;64:706e12. 12. Chiang MC, Tang JR, Yau KI, Yang CM. A proposal of screening guideline for retinopathy of prematurity in Taiwan. Acta Paediatr Taiwan 2002;43:204e7. 13. Liu PM, Fang PC, Huang CB, Kou HK, Chung MY, Yang YH, et al. Risk factors of retinopathy of prematurity in premature infants weighing less than 1600 g. Am J Perinatol 2005;22:115e20. 14. Yang KJ, Tsai CH, Lai CC, Lu CS, Chen TL. Retinopathy of prematurity: an evaluation in the Keelung area of Taiwan over a 10-year period. Chang Gung Med J 2005;28:39e43. 15. Wu WC, Ong FS, Kuo JZ, Lai CC, Wang NC, Chen KJ, et al. Retinopathy of prematurity and maternal age. Retina 2010;30: 327e31. 16. Fang PC, Kuo HK, Ko TY, Chen CC, Hwang KP, Chung MY. Retinopathy of prematurity in larger preterm infants. Am J Perinatol 2006;23:273e7. 17. Chung MY, Fang PC, Chung CH, Chen CC, Hwang KP, Chen FS. Comparison of neonatal outcome for inborn and outborn very low-birthweight preterm infants. Pediatr Int 2009;51:233e6. 18. Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology 2011;118:176e83. 19. Yang CS, Wang AG, Sung CS, Hsu WM, Lee FL, Lee SM. Longterm visual outcomes of laser-treated threshold retinopathy of prematurity: a study of refractive status at 7 years. Eye 2010; 24:14e20. 20. Lin SS, Su BH, Lin TW, Lin HC, Peng CT. A comparison of survival in extremely low birth weight infants between periods 19971998 and 1998-2000. Acta Paediatr Taiwan 2002;43:193e8. 21. Mercier CE, Dunn MS, Ferrelli KR, Howard DB, Soll RF. Neurodevelopmental outcome of extremely low birth weight infants
M.-L. Li et al.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37.
38.
39.
40.
41.
from the Vermont Oxford network: 1998-2003. Neonatology 2010;97:329e38. American Academy of Pediatrics. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2001;108:809e11. Fielder AR, Robinson J, Shaw DE, Ng YK, Moseley MJ. Light and retinopathy of prematurity: does retinal location offer a clue? Pediatrics 1992;89:648e53. Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol 2009;148:451e8. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Moseley MJ, Ratib S, et al. Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurty. Pediatrics 2002;109:12e8. Wilkinson AR, Haines L, Head K, Fielder AR. UK retinopathy of prematurity guideline. Early Hum Dev 2008;84:71e4. Chou YH, Teng RJ, Yau KI, Yang CM. Retinopathy of prematurity: an analysis of risk factors. J Formos Med Assoc 1993;92: 440e5. Rowlands E, Ionides AC, Chinn S, Mackinnon H, Davey CC. Reduced incidence of retinopathy of prematurity. Br J Ophthalmol 2001;85:933e5. Chiang MF, Arons RR, Flynn JT, Starren JB. Incidence of retinopathy of prematurity from 1996 to 2000: analysis of a comprehensive New York state patient database. Ophthalmology 2004;111:1317e25. Lermann VL, Fortes Filho JB, Procianoy RS. The prevalence of retinopathy of prematurity in very low birth weight newborn infants. J Pediatr (Rio J) 2006;82:27e32. Fortes Filho JB, Eckert GU, Procianoy L, Barros CK, Procianoy RS. Incidence and risk factors for retinopathy of prematurity in very low and in extremely low birth weight infants in a unit-based approach in southern Brazil. Eye 2009;23:25e30. Higgins RD, Mendelsohn AL, DeFeo MJ, Ucsel R, HendricksMunoz KD. Antenatal dexamethasone and decreased severity of retinopathy of prematurity. Arch Ophthalmol 1998;116: 601e5. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989-1997. Pediatrics 1999;104:e26. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959e69. Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005;115:e518e25. Markestad T, Kaaresen PI, Ronnestad A, Reigstad H, Lossius K, Medbo S, et al. Early death, morbidity, and need of treatment among extremely premature infants. Pediatrics 2005;115: 1289e98. Piecuch RE, Leonard CH, Cooper BA, Sehring SA. Outcome of extremely low birth weight infants (500 to 999 grams) over a 12-year period. Pediatrics 1997;100:633e9. Chen Y, Li XX, Yin H, Gilbert C, Liang JH, Jiang YR, et al. Risk factors for retinopathy of prematurity in six neonatal intensive care units in Beijing, China. Br J Ophthalmol 2008;92:326e30. Hiraoka M, Watanabe T, Kawakami T, Ito R, Takigawa I, Suzumura H, et al. Retinopathy of prematurity in extremely low birth weight infants: a Tokyo multicenter study. Nippon Ganka Gakkai Zasshi 2004;108:600e5. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3þ retinopathy of prematurity. N Engl J Med 2011;364:603e15. Kim JE, Lee AC. Demographic changes and response to laser treatment in threshold retinopathy of prematurity: 10-year experience. J Pediatr Ophthalmol Strabismus 2010;47:231e5.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan 42. Repka MX, Tung B, Good WV, Shapiro M, Capone Jr A, Baker JD, et al. Outcome of eyes developing retinal detachment during the Early Treatment for Retinopathy of Prematurity Study (ETROP). Arch Ophthalmol 2006;124:24e30. 43. Wu WC, Drenser KA, Lai M, Capone A, Trese MT. Plasmin enzymeassisted vitrectomy for primary and reoperated eyes with stage 5 retinopathy of prematurity. Retina 2008;28(suppl.):S75e80. 44. McLoone EM, O’Keefe M, McLoone SF, Lanigan BM. Long-term refractive and biometric outcomes following diode laser therapy for retinopathy of prematurity. J AAPOS 2006;10:454e9. 45. Davitt BV, Dobson V, Good WV, Hardy RJ, Quinn GE, Siatkowski RM, et al. Prevalence of myopia at 9 months in infants with high- risk prethreshold retinopathy of prematurity. Ophthalmology 2005;112:1564e8. 46. Sahni J, Subhedar NV, Clark D. Treated threshold stage 3 versus spontaneously regressed subthreshold stage 3 retinopathy of prematurity: a study of motility, refractive, and anatomical outcomes at 6 months and 36 months. Br J Ophthalmol 2005; 89:154e9. 47. Chen TC, Tsai TH, Shih YF, Yeh PT, Yang CH, Hu FC, et al. Longterm evaluation of refractive status and optical components in
9
48.
49.
50. 51.
52.
eyes of children born prematurely. Invest Ophthalmol Vis Sci 2010;51:6140e8. Quinn GE, Dobson V, Repka MX. the Cryotherapy for Retinopathy of Prematurity Cooperative Group. Development of myopia in infants with birth weights less than 1251 grams. Ophthalmology 1992;99:329e40. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Ratib S, Fielder AR. Change of refractive state and eye size in children of birth weight less than 1701 g. Br J Ophthalmol 2006;90: 456e60. Tasman W. Late complications of retrolental fibroplasia. Ophthalmology 1979;86:1724e40. Schaffer DB, Palmer EA, Plotsky DFand the Cryotherapy for Retinopathy of Prematurity Cooperative Group. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmology 1993;100:230e7. Ahmed MA, Duncan M, Kent A. Incidence of retinopathy of prematurity requiring treatment in infants born greater than 30 weeks’ gestation and with a birthweight greater than 1250 g from 1998 to 2002: a regional study. J Paediatr Child Health 2006;42:337e40.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
MODEL
Journal of the Formosan Medical Association (2012) xx, 1e9
Available online at www.sciencedirect.com
journal homepage: www.jfma-online.com
ORIGINAL ARTICLE
Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study Mei-Lun Li a, Sheng-Min Hsu a,b, Yi-Sheng Chang a,b, Min-Hsiu Shih a, Yung-Chieh Lin c, Chyi-Her Lin c, Hui-Ju Tsai d, Sung-Huei Tseng a,* a
Department of Ophthalmology, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan c Department of Pediatrics, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan d Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan b
Received 13 January 2011; received in revised form 1 March 2012; accepted 6 March 2012
KEYWORDS refractive outcomes; retinopathy of prematurity; risk factors; treatment
Background/Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. This retrospective study investigated ROP, including incidence, demographic information,risk factors, treatments, and refractive outcomes, in southern Taiwan over a 10-year period. Methods: The authors retrieved the National Cheng Kung University Hospital database between the years 2000 and 2009 for newborns with a gestational age less than 32 weeks and/or with a birth weight less than 1500 g who had been screened for ROP. We recorded sex, birth weight, gestational age, in-hospital versus out-of-hospital birth, paternal and maternal ages, whether there were multiple gestations, parity, Apgar scores, length of hospital stay, risk factors, presence and severity of ROP and whether it was treated, and refraction at the last visit. Regression analyses were performed to identify risk factors for ROP. Results: A total of 503 live births were included. ROP was identified in 190 (37.8%) and met criteria for treatment in 59 (11.7%).ROP was diagnosed as stage 1, 2, 3, 4, and 5 in 61 (12.1%), 36 (7.2%), 81 (16.1%), 11 (2.2%), and 1 (0.2%) infant, respectively. Lower birth weight and younger gestational age were risk factors for greater severity of ROP (p < 0.001). Of the 167 with extremely low birth weight (<1000 g), 118 (70.7%) had ROP and 49 (29.3%) required treatment.On univariate analysis, low birth weight, younger gestational age, and risk factorssuch as respiratory distress syndrome, chronic lung disease, patent ductus arteriosus, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis were associated with ROP. Multivariate logistic regression
* Corresponding author. Department of Ophthalmology, National Cheng Kung University College of Medicine and Hospital, 138 Sheng-Li Rd, Tainan, Taiwan. E-mail address: [email protected] (S.-H. Tseng). 0929-6646/$ - see front matter Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. doi:10.1016/j.jfma.2012.03.002
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
2
M.-L. Li et al. analysis showed that only lower birth weight was a significant and independent risk factor for ROP. Myopia (76%)and anisometropia (28%)were common in advanced ROP. Conclusion: Low birth weight is a major risk factor for ROP. Infants with extremely low birth weight had a higher risk of severe ROP. Common ocular sequelae of advanced ROP were myopia and anisometropia. Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Introduction Premature infants are at risk of retinopathy of prematurity (ROP), characterized by abnormal vascular development of the retina.1 ROP may progress rapidly to an advanced stage in which malformation of eye structures leads to blindness as a result of retinal detachment, macular folds, and refractive or strabismic amblyopia.1e4 The International Classification of Retinopathy of Prematurity (ICROP) allows for comparison of the incidences and outcomes of this disease across populations.1,5 Previous large-scale studies such as the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)2,5,6 and Early Treatment of Retinopathy of Prematurity (ETROP)7 studies showed that early intervention is effective in preventing loss of visual acuity and adverse anatomic outcomes. Despite increased awareness of and improved treatments for ROP, however, this disease remains a leading cause of childhood blindness, accounting for up to 10% of cases in developed countries.8 A number of ROP studies have been conducted in Taiwan, reporting on the incidence,9e15 characteristics,9e11,13e17 treatment options,14,18 and visual outcomes of ROP. 14,19 Over the past decade, medical care for neonates in Taiwan has advanced greatly, as evidenced by the increased survival rate of low-birth-weight (BW) infants, including those with very low birth weight (VLBW) (<1500 g) and those with extremely low birth weight (ELBW) (<1000 g).9,20,21 As a result of these increased survival rates, ophthalmologists are to examine more infants for evaluation of ROP. We conducted the study to investigate the incidence, severity, treatment and treatment outcomes, and the risk factors for ROP among low BW infants at a tertiary medical center in southern Taiwan for the 10-year period from 2000 through 2009.
study protocol was approved by the institutional review board of National Cheng Kung University Hospital.
Retinopathy assessment ROP was staged using ICROP.1,5 The first ROP screening examination for infants born before 27 weeks GA was carried out at 31 to 33 weeks postmenstrual age and that for infants born between 27 and 32 weeks GA was undertaken at 4 weeks postnatal age. For this examination, both pupils were dilated by instillingone drop of 0.5% tropicamide and 0.5% phenylephrine three times until full dilation occurred. Indirect ophthalmoscopy was performed using a lid speculum and scleral indentation. The stage of ROP was not determined by just one single examination. Instead, the eyes were reexamined on a weekly or biweekly basis, depending on the fundus findings of the screening examination. Eyes without ROP were reexamined biweekly by retinal specialists (Drs Li, Hsu, and Chang) until full vascularization of the retina was achieved. Those with ROP were examined every week until regression occurred or until ROP reached the threshold for laser or cryotherapy treatment.7 The highest stage of ROP recorded was assigned to each infant. From 2000 until the end of 2007, eyes were treated if they met the ICROP classification1,5 for threshold disease, which is defined as stage 2 ROP with plus disease with 5 contiguous clock hours of disease or a total of 8 noncontiguous clock hours in zone 1 or 2.22 After 2007, eyes were treated if they had type 1 ROP according to the ETROP criteria,7 in which type 1 ROP was defined as (1) any stage with plus disease in zone I, or (2) stage 3 ROP without plus disease in zone I, or (3) disease in zone II that was at stage 2 or 3 with plus disease. Eyes with threshold ROP or type 1 ROP were treated with indirect diode laser photocoagulation or cryotherapy under general anesthesia.
Methods Assessment of risk factors for ROP Case identification This is a retrospective study reviewing of medical records at National Cheng Kung University Hospital, a tertiary referral hospital in southern Taiwan, for all infants with either BW < 1500 g or gestational age (GA) < 32 weeks admitted between January 1, 2000, and December 31, 2009. We excluded those infants who failed to survive longer than 28 days for the first ROP screening, who did not live for 6 months postnatally to complete ROP screening, and who had congenital diseases such as chromosomal anomaly. The
In addition to BW and GA, we assessed the following for association with ROP: in-hospital or out-of-hospital birth, paternal age, maternal age, multiple gestations, parity, Apgar scores at 1 minute and 5 minutes, length of hospital stay, respiratory distress syndrome (RDS), mechanical ventilation, chronic lung disease (CLD), patent ductus arteriosus (PDA), prenatal maternal usage of steroid, postnatal surfactant use, postnatal indomethacin use, sepsis, intraventricular hemorrhage, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan
3
Refraction Cycloplegic refraction of the eyes was performed using a desktop computer autorefractometer (Topcon Corporation, Tokyo, Japan) after instilling onedrop of 0.5% tropicamide and 0.5% phenylephrine three times until the pupil dilated. Infants who were too small for desktop computer autorefractometry were assessed using retinoscopy. Refractive error values were converted to the spherical equivalent (SE).Myopia worse than -6.0 diopters (D) was considered to be advanced myopia. Anisometropia, or two eyes that have unequal power, greater than 1.5 D, was considered to be significant anisometropia. Refractive status was recorded at the age of the last ophthalmic visit.
Statistical analyses Statistical analyses were performed using the statistical package for social sciences software (SPSS 17.0 for Windows, SPSS Inc., Chicago, IL, USA) and Microsoft Excel software (Microsoft Corporation, Redmond, WA, USA). Descriptive statistics were expressed as mean 1 standard deviation. The chi-square test was used to compare categoric data related to clinical outcomes. Student t test and analysis of variance were used to compare continuous data. Univariate analyses were used to test for the potential risk
factors of ROP. If significant at p < 0.05, risk factors were included in the stepwise multivariable logistic regression analyses. The adjusted odds ratio and corresponding 95% confidence interval for the incidence of ROP was calculated for the risk factors in the model.
Results Patient characteristics Five hundred three infants (255 male and 248 female) met the criteria for inclusion in this study. Their BWs ranged from 455 to 1968 g (1157 313) and GA ranged from 21 to 38 weeks (29.1 2.7). ROP was identified in 190 infants (37.8%), and 59 infants (11.7%) underwent laser photocoagulation therapy or cryotherapy. Table 1 summarizes the characteristics of the 503 infants with or without ROP on the screening examination. There was a statistically significant difference in BW for infants with and without ROP (mean BW for those with ROP Z 940 251 g vs. 1288 272 g for those without ROP, p < 0.001). Of the 503 infants, 435 had very low BW (VLBW) (<1500 g), and 185 (42.5%) of the 435 had ROP. However, of the 167 with extremely low BW (ELBW) (<1000 g), 118 (70.7%) had ROP, compared with only 49 (29.3%) of those without ROP. As for the remaining 68 newborns weighing
Table 1 Characteristics of 503 premature infants with or without retinopathy of prematurity on initial screening, 2000-2009 (univariate analysis). Characteristic
Infants with ROP, n Z 190 (37.8%)
Infants without ROP, n Z 313 (62.2%)
p Value
Sex (% male)
101 (53.2)
154 (49.2)
Birth weight (g), number (%) <750 750-999 1000-1249 1250-1499 >1500 Mean (1 SD)
35 (18.4) 83 (43.7) 52 (27.4) 15 (7.9) 5 (2.6) 940 ( 251)
8 (2.6) 41 (13.1) 84 (26.8) 117 (37.4) 63 (20.1) 1288 ( 272)
<0.001
Gestational age (weeks), number (%) <26 26-28 29-31 32-38 Mean (1 SD )
52 (27.4) 99 (52.1) 28 (14.7) 11 (5.8) 27.0 (2.4)
4 (1.3) 64 (20.4) 173 (55.3) 72 (23.0) 30.1 (2.1)
<0.001
Out-of-hospital birth
33.5%
26.3%
0.106
Other characteristics, mean 1 SD Paternal age (years) Maternal age (years) Multiple gestation Parity (number) Apgar score, 1 minute Apgar score, 5 minutes Length of hospital stay (days)
34.1 5.6 31.5 5.0 2.3 1.4 1.7 0.8 4.7 2.0 6.9 1.8 66.2 39.8
33.4 6.0 29.9 5.3 2.1 1.8 1.6 0.7 5.6 2.0 7.8 1.7 45.1 33.5
0.406 0.006 0.330 0.064 <0.001 <0.001 <0.001
ROP Z retinopathy of prematurity; SD Z standard deviation.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
4
M.-L. Li et al.
>1500 g, only 5 (7.4%) screened positive for ROP and none of them required treatment. There was also a statistically significant difference in GA between infants with and those without ROP (GA 27.0 2.4 weeks for those with ROP vs. 30.1 2.1 weeks for those without ROP, p < 0.001). Additionally, ROP was more prevalent among infants born to older mothers, those with lower Apgar scores, and those with prolonged hospital stays (Table 1).
Correlation of stage of ROP with BW and GA As shown in Table 2, the stage of ROP correlated inversely with BW and GA. On average, infants with BWs < 900 g were more likely to develop threshold ROP or even more advanced stages that required treatment; however, there were a number of newborns weighing <900 g with ROP who did not reach the threshold level for treatment.Likewise, the mean BW of infants undergoing treatment for ROP was significantly lower than those with ROP not requiring treatment and lower than those without ROP (819 214 vs. 995 248 vs. 1288 272 g, p < 0.001)(Table 3). Fig. 1 shows the proportions of infants with treated ROP, untreated ROP, and no ROP, by BW. Among infants with VLBW and ELBW, 13.6 % and 29.3%, respectively, required treatment for ROP. A similar correlation was seen for GA, which was significantly lower for infants with ROP who required treatment compared with those with ROP not requiring treatment and those without ROP (26.4 2.7 vs. 27.4 2.5 vs. 30.2 2.7 weeks, p < 0.001) (Table 3). Overall, among infants with a GA < 32 weeks versus >32 weeks, ROP was diagnosed in 42.6% versus 13.3%, respectively. Fig. 2 shows the proportions of infants with treated ROP, untreated ROP, and no ROP, by GA. Among infants with GA < 26weeks, 26-28 weeks, 29-31 weeks, and > 32 weeks, treatment for ROP was required by 42.9%, 16.7%, 3.4%, and 1.2%, respectively. Only one infant in the >32-week GA group (GA Z 33 weeks) required treatment for ROP and this infant had a BW of 1120 g. After the treatment (retinal photocoagulation or cryotherapy), ROP regressed in 83.1% (n Z 49) of the treated infants. In the other 16.9% (n Z 10), ROP progressed to either stage 4 or 5 and required further surgical intervention.
Table 2
Refractive status of infants with ROP A total of 113 infants (55 male and 58 female) were brought back to the hospital for refractive examination. The mean age at this examination was 2.7 2.5 years (range, 0.2 to 9.7 years). Mean refractive error in these 113 infants was close to emmetropia (0.02 3.23 D), although the ranges were large (þ7.25 to -13.50 D). Of these 113 infants, 25 (50 eyes) had undergone treatment for ROP. Three of them progressed to stage 4 and the others regressed. As shown in Fig. 3, the 50 eyes that were treated for ROP had SEs of -3.50 4.27 D; 38 (76.0%) of these 50 eyes were myopic. Mean SEs in eyes with untreated ROP were 0.53 2.13 D,which were close to emmetropia,and eyes without ROP had mean SEs of 1.57 1.53 D. Advanced myopia (<-6.0 D) was noted in only 10 of 113 infants (8.4%), but in 17 eyes of 50 treated eyes (34.0%) (p < 0.001). Significant anisometropia (>1.5 D) was present in 12 of 113 infants (10.6%) and was found in a higher proportion of infants with treated ROP (n Z 7) compared with untreated ROP (n Z 5) or no ROP (n Z 0) (28.0%, 11.1%, and 0% respectively), and the differences were significant (pZ 0.004).
Risk factors for ROP On univariate analysis, patient characteristics associated with ROP were lower BW, younger GA, lower Apgar scores at 1 minute and 5 minutes, and longer length of hospital stay (Table 1). In addition, a significantly higher proportion of infants with ROP versus those without ROP had RDS, CLD, PDA, administration of surfactant or indomethacin, sepsis, upper gastrointestinal bleeding, blood transfusion, or necrotizing enterocolitis (Table 4). However, the stepwise multivariate logistic regression analysis showed that only low BW (adjusted odds ratio 0.996 [95% confidence interval 0.993-0.998]) was predictive of the development of ROP.
Discussion In our study, higher incidence of ROP has a significant association with lower BW, younger GA,lower Apgar scores at 1 minute and 5 minutes, longer length of hospital stay,
Maximum ROP stage on screening of 503 infants, by birth weight and gestational age.
Maximum ROP stage
Number (%)
Birth weight in grams, mean 1 SD (range)
Gestational age in weeks mean 1 SD (range)
None Stage 1 Stage 2 Stage 3 Subthreshold Threshold (3þ) Stage 4 Stage 5 Total patients
313 (62.2) 61 (12.1) 36 (7.2) 34 (6.8) 47 (9.3) 11 (2.2) 1 (0.2) 503 (100)
1288 272 (542-1968) 1030 238 (455-1716) 960 236 (472-1480) 969 274 (560-1760) 817 201 (460-1438) 841 275 (600-1484) 660 1157 313 (455-1968)
30 2.1 (23-36) 28 2.4 (24-38) 27 2.3 (24-35) 26 2.3 (21-30) 26 1.8 (23-32) 26 2.9 (24-33) 24 29.1 2.7 (21-38)
ROP Z retinopathy of prematurity; SD Z standard deviation.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan Table 3
5
Mean BW and GA in no ROP, untreated ROP, and treated ROP groups.
Mean BW 1 SD (g) Mean GA 1 SD (weeks)
No ROP, n Z 313 (62.2%)
Untreated ROP, n Z 131 (26.0%)
Treated ROP, n Z 59 (11.7%)
p Value
1288 272 30.2 2.7
995 248 27.4 2.5
819 214 26.4 2.7
<0.001 <0.001
BW Z birth weight; GA Z gestational age; ROP Z retinopathy of prematurity; SD Z standard deviation.
RDS, CLD, PDA, administration of surfactant or indomethacin, and sepsis, upper gastrointestinal bleeding, blood transfusion, or necrotizing enterocolitis on univariate analysis. However, on multivariate analysis, higher risk of ROP was predicted only by BW. Risk factors reported in the literature vary, in many cases attributable to differences in methodology, screening criteria, and indications for treatment of ROP. Regarding the relative predictive value of BW and GA, although GA is highly correlated with BW, a number of studies23,24 have previously reported that BW is a stronger predictor of ROP than GA. When compared with full-term infants, low BW infants are especially at increased risk of visual impairment.25 Two explanations for these findings have been given: (1) the high error rate when GA is estimated based on prenatal ultrasound results and (2) the possibility that premature infants with intrauterine growth retardation might be at higher risk of developing ROP because of their eventful clinical course, with conditions such as RDS, sepsis, upper gastrointestinal bleeding, necrotizing enterocolitis, and failure to thrive. Regarding variations in screening criteria, the Royal College of Pediatrics and Child Health (RCPCH)26 has recommended that infants with BW < 1501 g and/or GA < 32 weeks be screened for ROP, whereas the American Academy of Pediatrics has proposed screening for those with BW < 1500 g and/or GA < 28 weeks.22 The screening criteria we used in the study reported here are consistent with those of the RCPCH. Even so, one infant who, at a GA of 32 weeks and BW of 1760 g, did not meet RCPCH
Figure 1
guidelines for screening, developed stage 3 ROP in his right eye. He was not born in a neonatal center, had an older mother (37 years old), 1-minute Apgar score of 4, and received supplemental oxygen for the first 3 days of life. Although stage 3 ROP regressed spontaneously without treatment in this case, it reminds us that some infants with severe ROP might not meet current screening criteria. Regarding what additional factors might predict the need for screening, Fang et al.16 recommend that larger preterm infants should be screened for ROP if they have lower 1minute Apgar scores, oxygen supplementation more than 40% or for longer than 5 days, or an unstable clinical course. To these criteria, we would add, based on the study reported here, older maternal age, lower 5-minute as well as 1-minute Apgar scores,and oxygen supplementation as criteria for ROP screening. Regarding the relationship of ROP to BW and GA, ROP was diagnosed in 37.8% of 503 infants with GA < 32 weeks or BW < 1500 g. Among VLBW infants (<1500 g), the incidence of ROP was 42.5% and among ELBW infants (<1000 g) the incidence was 70.7%. Our overall incidence and incidence among VLBW infants are comparable to the 42.5% incidence of ROP reported in Taiwan between 1988 and 199127and a 36.5% incidence reported for the period 1996 to 2000.13 Among older premature infants (GA < 37 weeks), Wu et al.15 reported an incidence of ROP of just 13%. In the CRYO-ROP trial, the incidence of ROP was 65.8% among infants with BW < 1250 g and 81.6% in ELBW infants. Compared to this most widely cited CRYO-ROP study conducted in the mid-1980s, our results show
Rates of retinopathy of prematurity (ROP) stratified by birth weight (BW) and treatment.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
6
M.-L. Li et al.
Figure 2
Rates of retinopathy of prematurity (ROP) stratified by gestational age (GA) and treatment.
approximately 10% lower incidences of ROP for infantswith BW < 1250 g (56.1%) and ELBW (70.7%). Results similar to ours, however, were reported in a Taiwan study (36.5% incidence in infants <1600 g and 59.5 % incidence in ELBW infants).13 In studies conducted among western populations, incidences of ROP ranged between 15.7% and 48.9%,28e31 with a trend toward lower rates over time. This trend has been attributed to improvements in care for premature infants, such as surfactant prophylaxis to improve pulmonary maturity, continuous pulse oximetry, antenatal maternal steroids, and use oflower concentrations of oxygen.32e34 Without long-term longitudinal studies conducted among the same population using the same criteria, it is difficult for us to determine whether the incidence of ROP is changing in Taiwan. As the numbers of infants with ELBW and VLBW who survive increase,9,20,21,35,36 more infants are likely to require screening for ROP. Moreover, as improvements in care lead to survival of more ELBW infants without major neurologic or cognitive deficits,37 detection and treatment
10
Spherical equivalent (D)
5
0
-5
-10
-15
Treated ROP (n=25)
Untreated ROP (n=45)
No ROP (n=43)
Figure 3 Comparisons of refractive status among treated retinopathy of prematurity (ROP), untreated ROP, and no ROP groups. D Z diopter.
of ROP will be increasingly important to ensure optimal quality of life for these patients. In the study we report here, the incidence of treated ROP was 29.3% among ELBW infants. Incidences of ROP meeting treatment criteria in other recent domestic studies13e15 differ from ours depending on study criteria. Yang et at.14 reported an incidence of 13.5% for ROP requiring treatment between 1994 and 2003, whereas Liu et at.13 reported a lower incidence of ROP requiring treatment (8.2%) in premature infants weighing <1600 g. However, in a Beijing study,38 the incidence of treated ROP was 28.6% and 28.7% in a study of ELBW infants in the United States.24 Both findings are comparable to our results. Nonetheless, a study among Japanese infants found indications for treatment in up to 41%, which might be attributed to an 86.1% incidence of ROP for ELBW infants.39 However, only 17.0% of ELBW infants in a Brazil study were treated.31 Retinal neovascularization leads to retinal traction, retinal hemorrhage, and retinal detachment, finally affecting vision. In the past decade, the recommended treatment for type 1 and threshold ROP was peripheral ablation, and laser therapy was the preferred method of treatment rather than cryotherapy. However, the use of anti-vascular endothelial growth factor agents, primarily intravitreal bevacizumab, is currently an emerging treatment for type 1 and threshold ROP s.40 Off-label use of intravitreal bevacizumab therapy as monotherapy and in combination with conventional laser therapy or vitrectomy or both18 are current treatment options for type 1 and threshold ROP and the results seem promising. In our study, regression of retinal neovascularization was noted in 83.1% of the infants whose disease was treated. Our result is similar to that in the CRYO-ROP study,6 in which 74% of the eyes had a favorable outcome at 1 year, and almost the same as the 84% with a favorable outcome in the conventional treatment arm of the ETROP trial7 at 9 months. Our result is comparable as well to results in other published studies.6,7,40,41 Although laser therapy or cryotherapy effectively halts the progression of stage 3 to 4 ROP in most patients, these treatments actually destroy the peripheral retina and may lead to visual field defect and refractive changes. Therefore, the new treatment option, intravitreal bevacizumab therapy, may prevent visual field defect,
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan Table 4
7
Risk factors in newborns with or without retinopathy of prematurity (ROP) (univariate analysis).
Risk factors
Newborns without ROP, n Z 313
Newborns with ROP, n Z 190
p Value
Respiratory distress syndrome* Mechanical ventilation Chronic lung disease* Patent ductus arteriosus* Steroid exposure prenatally Surfactant usage* Indomethacin usage* Sepsis* Intraventricular hemorrhage Upper gastrointestinal bleeding* Blood transfusion* Necrotizing enterocolitis*
67.7% 86.9% 27.0% 39.6% 72.8% 26.9% 42.9% 41.6% 19.2% 16.0% 37.6% 15.7%
86.2% 84.2% 64.8% 58.5% 78.5% 53.1% 71.7% 61.2% 26.3% 34.6% 58.1% 26.1%
<0.001 0.57 <0.001 0.001 0.224 <0.001 <0.001 <0.001 0.113 <0.001 <0.001 0.006
*Statistically significant at the level of p < 0.05.
especially in zone I ROP patients,40 and decrease the possibility of progression to stage 4 or 5 after peripheral ablation, whereby functional visual outcomes are still not satisfying, even after vitrectomy or scleral buckling.42,43 Major concerns for premature infants, particularly those with ROP, are development of the eye, refractive status, and visual outcome. In the current study with an average follow-up of 2.7 years,the mean refractive errors of eyes without ROP, with untreated ROP, treated ROP were þ1.5 D, þ0.5 D, and -3.5 D, respectively.Approximately 75% of treated eyes in our study had myopia and approximately 25% hadadvanced myopia (<-6.0 D).Yang et al19 reported similar results in a recent domestic study: 77% of lasertreated eyes were myopic and 16.7% had worse than -6.0 D of myopia at an average patient age of 7 years. Rates of myopia may vary among studies because the incidence of myopia increases with increasing prematurity and severity of ROP.44e46 Myopia in infants with ROP is believed to be partly due to the disease process of ROP and partly a result of therapy for ROP. Factors accounting for this relationship include anomalies of corneal diameter and curvature, shorter anterior chamber, axial length, thicker lens, and laser effects on the sclera.6,44,47,48 A combination of various optical components results in complicated refractive outcomes. Another study found that lower BW and greater severity of ROP strongly predicted myopia and high myopia.25,47,49 Of note, Tasman50 reported that patients withROP and a high degree of myopia had a higher rate of retinal detachment in later life. This indication that ROP has lifelong consequences means that long-term follow-up is crucial for patients with treated ROP. The risk factors for ROP we identified in univariate analysis (RDS, CLD, PDA, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis) are in line with findings in other studies that ROP is associated with complex medical conditions that require prolonged treatment with oxygen.29,51,52 However, lower BW was the most important predictor of ROP. Our study has three major limitations. The first is its design, as a retrospective study with relatively small sample size compared with some other studies in the
literature.2,4,6,7,24,29,45,49 Ideally, a large, carefully designed population-based cohort study should be conducted of ROP throughout Taiwan. Second, the incidence of ROP in our study simply represented the clinical observations of premature infants at a single tertiary medical center and could not reflect the exact incidence of ROP in the area of southern Taiwan. Third, the refractive status in our study was examined at different ages among the study participants. This lack of a standardized age for final evaluation made it difficult to generalize and compare results among the study groups. An ideal study would measure refractive outcomes, optical components, and functional outcomes, such as visual acuity, at standardized ages over the long term, to assess the risk for amblyopia and other sequelae of ROP at various times/ages after treatment. In conclusion, our study confirmed the findings in previous studies that low BW significantly increases the risk for ROP. ELBW infants are at even higher risk of ROP and of more advanced ROP requiring immediate treatment compared with those with VLBW. Myopia and subsequent amblyopia and other ocular sequelae of ROP may cause lifelong problems.
Financial support None.
Acknowledgments The authors are grateful to Dr Sheng-Hsiang Lin and Ms Shang-Chi Lee of the Research Center for Clinical Medicine, National Cheng Kung University Hospital, for providing statistical analyses.
References 1. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130e4.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
8 2. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 1/2 years after randomization. Arch Ophthalmol 1996;114: 417e24. 3. Bremer DL, Palmer EA, Fellows RR, Baker JD, Hardy RJ, Tung B, et al. Strabismus in premature infants in the first year of life. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1998;116:329e33. 4. Quinn GE, Dobson V, Kivlin J, Kaufman LM, Repka MX, Reynolds JD, et al. Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1998;105:1292e300. 5. International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. Arch Ophthalmol 1987;105:906e12. 6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Status at 1 year. Arch Ophthalmol 1994;112: 903e12. 7. Early Treatment for Retinopathy of Prematurity Cooperative G. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121: 1684e94. 8. Steinkuller PG, Du L, Gilbert C, Foster A, Collins ML, Coats DK. Childhood blindness. J AAPOS 1999;3:26e32. 9. Lin HJ, Lin CC, Tsai SW, Lin HC, Su BH. Risk factors for retinopathy of prematurity in very low birth-weight infants. J Chin Med Assoc 2003;66:662e8. 10. Yang CM, Liu KR, Chen MS, Ko LS. Ocular fundus examination in premature infants. J Formos Med Assoc 1991;90:480e6. 11. Yang CS, Chen SJ, Lee FL, Hsu WM, Liu JH. Retinopathy of prematurity: screening, incidence and risk factors analysis. Zhonghua Yi Xue Za Zhi (Taipei) 2001;64:706e12. 12. Chiang MC, Tang JR, Yau KI, Yang CM. A proposal of screening guideline for retinopathy of prematurity in Taiwan. Acta Paediatr Taiwan 2002;43:204e7. 13. Liu PM, Fang PC, Huang CB, Kou HK, Chung MY, Yang YH, et al. Risk factors of retinopathy of prematurity in premature infants weighing less than 1600 g. Am J Perinatol 2005;22:115e20. 14. Yang KJ, Tsai CH, Lai CC, Lu CS, Chen TL. Retinopathy of prematurity: an evaluation in the Keelung area of Taiwan over a 10-year period. Chang Gung Med J 2005;28:39e43. 15. Wu WC, Ong FS, Kuo JZ, Lai CC, Wang NC, Chen KJ, et al. Retinopathy of prematurity and maternal age. Retina 2010;30: 327e31. 16. Fang PC, Kuo HK, Ko TY, Chen CC, Hwang KP, Chung MY. Retinopathy of prematurity in larger preterm infants. Am J Perinatol 2006;23:273e7. 17. Chung MY, Fang PC, Chung CH, Chen CC, Hwang KP, Chen FS. Comparison of neonatal outcome for inborn and outborn very low-birthweight preterm infants. Pediatr Int 2009;51:233e6. 18. Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology 2011;118:176e83. 19. Yang CS, Wang AG, Sung CS, Hsu WM, Lee FL, Lee SM. Longterm visual outcomes of laser-treated threshold retinopathy of prematurity: a study of refractive status at 7 years. Eye 2010; 24:14e20. 20. Lin SS, Su BH, Lin TW, Lin HC, Peng CT. A comparison of survival in extremely low birth weight infants between periods 19971998 and 1998-2000. Acta Paediatr Taiwan 2002;43:193e8. 21. Mercier CE, Dunn MS, Ferrelli KR, Howard DB, Soll RF. Neurodevelopmental outcome of extremely low birth weight infants
M.-L. Li et al.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37.
38.
39.
40.
41.
from the Vermont Oxford network: 1998-2003. Neonatology 2010;97:329e38. American Academy of Pediatrics. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2001;108:809e11. Fielder AR, Robinson J, Shaw DE, Ng YK, Moseley MJ. Light and retinopathy of prematurity: does retinal location offer a clue? Pediatrics 1992;89:648e53. Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol 2009;148:451e8. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Moseley MJ, Ratib S, et al. Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurty. Pediatrics 2002;109:12e8. Wilkinson AR, Haines L, Head K, Fielder AR. UK retinopathy of prematurity guideline. Early Hum Dev 2008;84:71e4. Chou YH, Teng RJ, Yau KI, Yang CM. Retinopathy of prematurity: an analysis of risk factors. J Formos Med Assoc 1993;92: 440e5. Rowlands E, Ionides AC, Chinn S, Mackinnon H, Davey CC. Reduced incidence of retinopathy of prematurity. Br J Ophthalmol 2001;85:933e5. Chiang MF, Arons RR, Flynn JT, Starren JB. Incidence of retinopathy of prematurity from 1996 to 2000: analysis of a comprehensive New York state patient database. Ophthalmology 2004;111:1317e25. Lermann VL, Fortes Filho JB, Procianoy RS. The prevalence of retinopathy of prematurity in very low birth weight newborn infants. J Pediatr (Rio J) 2006;82:27e32. Fortes Filho JB, Eckert GU, Procianoy L, Barros CK, Procianoy RS. Incidence and risk factors for retinopathy of prematurity in very low and in extremely low birth weight infants in a unit-based approach in southern Brazil. Eye 2009;23:25e30. Higgins RD, Mendelsohn AL, DeFeo MJ, Ucsel R, HendricksMunoz KD. Antenatal dexamethasone and decreased severity of retinopathy of prematurity. Arch Ophthalmol 1998;116: 601e5. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989-1997. Pediatrics 1999;104:e26. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959e69. Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005;115:e518e25. Markestad T, Kaaresen PI, Ronnestad A, Reigstad H, Lossius K, Medbo S, et al. Early death, morbidity, and need of treatment among extremely premature infants. Pediatrics 2005;115: 1289e98. Piecuch RE, Leonard CH, Cooper BA, Sehring SA. Outcome of extremely low birth weight infants (500 to 999 grams) over a 12-year period. Pediatrics 1997;100:633e9. Chen Y, Li XX, Yin H, Gilbert C, Liang JH, Jiang YR, et al. Risk factors for retinopathy of prematurity in six neonatal intensive care units in Beijing, China. Br J Ophthalmol 2008;92:326e30. Hiraoka M, Watanabe T, Kawakami T, Ito R, Takigawa I, Suzumura H, et al. Retinopathy of prematurity in extremely low birth weight infants: a Tokyo multicenter study. Nippon Ganka Gakkai Zasshi 2004;108:600e5. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3þ retinopathy of prematurity. N Engl J Med 2011;364:603e15. Kim JE, Lee AC. Demographic changes and response to laser treatment in threshold retinopathy of prematurity: 10-year experience. J Pediatr Ophthalmol Strabismus 2010;47:231e5.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002
+
MODEL
ROP in southern Taiwan 42. Repka MX, Tung B, Good WV, Shapiro M, Capone Jr A, Baker JD, et al. Outcome of eyes developing retinal detachment during the Early Treatment for Retinopathy of Prematurity Study (ETROP). Arch Ophthalmol 2006;124:24e30. 43. Wu WC, Drenser KA, Lai M, Capone A, Trese MT. Plasmin enzymeassisted vitrectomy for primary and reoperated eyes with stage 5 retinopathy of prematurity. Retina 2008;28(suppl.):S75e80. 44. McLoone EM, O’Keefe M, McLoone SF, Lanigan BM. Long-term refractive and biometric outcomes following diode laser therapy for retinopathy of prematurity. J AAPOS 2006;10:454e9. 45. Davitt BV, Dobson V, Good WV, Hardy RJ, Quinn GE, Siatkowski RM, et al. Prevalence of myopia at 9 months in infants with high- risk prethreshold retinopathy of prematurity. Ophthalmology 2005;112:1564e8. 46. Sahni J, Subhedar NV, Clark D. Treated threshold stage 3 versus spontaneously regressed subthreshold stage 3 retinopathy of prematurity: a study of motility, refractive, and anatomical outcomes at 6 months and 36 months. Br J Ophthalmol 2005; 89:154e9. 47. Chen TC, Tsai TH, Shih YF, Yeh PT, Yang CH, Hu FC, et al. Longterm evaluation of refractive status and optical components in
9
48.
49.
50. 51.
52.
eyes of children born prematurely. Invest Ophthalmol Vis Sci 2010;51:6140e8. Quinn GE, Dobson V, Repka MX. the Cryotherapy for Retinopathy of Prematurity Cooperative Group. Development of myopia in infants with birth weights less than 1251 grams. Ophthalmology 1992;99:329e40. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Ratib S, Fielder AR. Change of refractive state and eye size in children of birth weight less than 1701 g. Br J Ophthalmol 2006;90: 456e60. Tasman W. Late complications of retrolental fibroplasia. Ophthalmology 1979;86:1724e40. Schaffer DB, Palmer EA, Plotsky DFand the Cryotherapy for Retinopathy of Prematurity Cooperative Group. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmology 1993;100:230e7. Ahmed MA, Duncan M, Kent A. Incidence of retinopathy of prematurity requiring treatment in infants born greater than 30 weeks’ gestation and with a birthweight greater than 1250 g from 1998 to 2002: a regional study. J Paediatr Child Health 2006;42:337e40.
Please cite this article in press as: Li M-L, et al., Retinopathy of prematurity in southern Taiwan: A tertiary medical center 10-year study, Journal of the Formosan Medical Association (2012), doi:10.1016/j.jfma.2012.03.002