Int Ophthalmol DOI 10.1007/s10792-014-9956-2
ORIGINAL PAPER
Incidence and risk factors for retinopathy of prematurity in extreme low birth weight Chinese infants Gordon S. K. Yau • Jacky W. Y. Lee • Victor T. Y. Tam • Catherine C. L. Liu Benjamin C. Y. Chu • Can Y. F. Yuen
•
Received: 20 April 2014 / Accepted: 20 May 2014 Springer Science+Business Media Dordrecht 2014
Abstract The objective of this study is to determine the incidence and risk factors of retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) Chinese infants. A retrospective medical record review of all ELBW (B1,000 g) neonates screened for ROP from 2007 to 2012 was performed in Hong Kong. ROP screening was conducted at 2 neonatal intensive care units by 3 pediatric ophthalmologists using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. In 131 ELBW Chinese infants, the mean gestational age (GA) and birth weight (BW) were 27.3 ± 3.3 weeks and 806.9 ± 133.7 g, respectively. The incidence of ROP and Type 1 ROP was 53.4 and 14.5 %, respectively. For ROP, a lighter BW, smaller GA, vaginal delivery, postnatal hypotension, inotrope use, bronchopulmonary dysplasia, surfactant use, invasive
mechanical ventilation, and supplementary oxygen were independent risk factors for ROP, while PET was protective (P B 0.02). On multivariate analysis, a smaller GA was a risk factor, while PET and congenital heart disease were protective for ROP development (P B 0.01). For Type 1 ROP, a lighter BW, smaller GA, surfactant use, and invasive mechanical ventilation were independent risk factors for ROP, while PET was protective (P B 0.02). There were no significant covariates on multivariate analysis for Type 1 ROP. In ELBW, preterm Chinese infants, a smaller GA was a risk factor for ROP, while PET and congenital heart disease were protective for ROP development in multivariate analysis. Keywords Retinopathy of prematurity ROP Extreme low birth weight Chinese Risk factors
Introduction G. S. K. Yau (&) J. W. Y. Lee V. T. Y. Tam B. C. Y. Chu C. Y. F. Yuen The Department of Ophthalmology, Caritas Medical Centre, 111 Wing Hong Street, Kowloon, Hong Kong SAR, People’s Republic of China e-mail: [email protected] C. C. L. Liu Department of Applied Mathematics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, People’s Republic of China
Retinopathy of prematurity (ROP) is a vasoproliferative disease targeting the developing retina particularly in those with low birth weight and preterm gestation [1]. ROP is one of the leading causes of childhood blindness in developed nations [2]. It is no longer uncommon for extremely low birth weight (ELBW, B1,000 g) neonates to survive following the advances in neonatal intensive unit care over the past decades [3–5], thus, understanding the
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Treatment for Retinopathy of Prematurity (ETROP) study [9]. The staging of ROP was recorded according to the revised International Classification of ROP, including the extent, zone, and the presence or absence of ‘‘plus’’ disease [10]. Type 1 ROP was defined as high risk prethreshold ROP, with either one of the following features: (i) Zone I, any stage ROP with plus disease (C2 quadrant involvement as per the ETROP Study); (ii) Zone I, stage 3 ROP with or without plus disease; or (iii) Zone II, stage 2 or 3 ROP with plus disease [9].
determinants of ROP development in this particular group of ELBW neonates is clinically relevant. While Hong Kong has a comparable standard of medical care to its Western counterparts [6], there is a paucity of data in the literature reporting the incidence and associations of ROP among ELWB Chinese infants using newer international guidelines such as the Royal College of Ophthalmologists and United Kingdom (UK)-ROP Guidelines [7, 8]. The aim of this study was to analyze occurrence and associations of ROP among ELBW preterm infants in the Chinese population.
Patients and methods The study was approved by the Institutional Review Board of the Hospital Authority of Hong Kong. The study was conducted in accordance with the Declaration of Helsinki, and no patient personal data were disclosed in the study. The authors declare no financial or proprietary interests. This was a retrospective study conducted at Caritas Medical Centre, Hong Kong Special Administrative Region, China, which provides ophthalmological service to 2 neonatal intensive care units (NICU) for a population of 1.8 million. Medical records for consecutive subjects screened for ROP between the period of January 2007 and December 2012 were retrieved using the Clinical Data Record System of the Hospital Authority of Hong Kong. ROP screening criterion •
All preterm babies admitted to these 2 NICU’s with a birth weight (BW) B1,500 g and/or gestational age (GA) B32 weeks were referred to a pediatric ophthalmologist for evaluation. All eligible preterms were examined according to the screening protocol recommended by the Royal College of Ophthalmologists and UK-ROP) guidelines [9, 10]. Subjects were first screened at 4–8 weeks of postnatal age (C30 week GA) and were examined weekly to bi-weekly, until retinal vascularisation reached zone 3 or feature of established ROP regression [9]. Treatment was diode laser which was implemented when the disease progressed to Type 1 ROP as per the Early
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All examinations were performed by three experienced pediatric ophthalmologists (SKY, TYT, CYC). Each infant was screened by an indirect ophthalmoscope using a 30-diopter lens after full pharmacological pupil dilatation with tropicamide 0.5 % and phenylephrine 1 % eye drops. A lid speculum with scleral indentation after topical anesthesia (amethocaine) was routinely used. All screenings were performed under oxygen saturation monitoring and the screening was temporarily withheld in case of desaturations. The inclusion criteria included all subjects with BW B1,000 g (ELBW) that underwent ROP screening. Neonates with incomplete clinical data or those that were diseased before the completion of ROP screening were excluded. The primary outcome measures included: the severity of ROP (the extent, zone, and the presence or absence of ‘‘plus’’ disease) as well as the 34 risk factors (both maternal and neonatal) for the development of ROP as follows: Antenatal maternal risk factors: (Table 1) •
• • •
Maternal diseases: pre-eclampsia (PET), gestational diabetes mellitus (GDM), order of pregnancy (singleton or multiple gestations). In-vitro fertilization (IVF). Use of antenatal steroid (ANS). Mode of delivery (Cesarean section versus vaginal delivery).
Neonatal risk factors: (Table 1) • •
Demographic information (GA, BW, gender); Apgar Scores at 1, 5, and 10 min;
1.18 1.28 0.89
\0.001ab \0.001ab 0.01ab 0.85 0.09 0.69
Delivery (Caesarian vs. vaginal)
Postnatal hypotension
Inotropes use
Antenatal steroid use
Apgar score 1 min
Apgar score 5 min
Apgar score 10 min
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
\0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b
Oxygen supplement
Mean oxygen concentration, FiO2 (%)
Congenital heart disease
Patent ductus arteriosus NSAID use
Anemia
Thrombocytopenia
Blood transfusion
Intraventricular hemorrhage 0.00 0.00
\0.001 \0.001b \0.001b
Necrotizing colitis
Neonatal janice
Phototherapy
0.00
NA
\0.001ab
Invasive mechanical ventilation
b
1.55
\0.001
Surfactant use 1.70
0.91
0.01ab
Bronchopulmonary dysplasia ab
-0.06 16.81
0.64 \0.001ab
Respiratory distress syndrome
-0.03
-0.15
0.08
-0.45 -0.15
–0.03 -1.93
0.94 0.56 0.82
Gestational diabetes mellitus In-vitro fertilization
Pre-eclampsia
\0.001ab
-0.01
\0.001ab
Birth weight
Multiple pregnancies
-0.22 -0.85
0.55 \0.001ab
0.80
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
NA
4.73
5.45
2.48
19919910.00
0.94
0.97
0.86
1.08
2.44
3.58
3.26
0.64 0.86
0.14
0.97
0.99
0.43
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.92
2.23
1.22
0.00
0.71
0.81
0.71
0.46
1.19
1.75
1.61
0.12 0.23
0.05
0.38
0.99
0.31
0.39
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
12.93
14.85
5.15
NA
1.22
1.15
1.02
2.54
5.15
7.56
6.81
3.01 3.24
0.37
2.48
1.00
0.56
1.64
95 % confidence interval
Odds ratio
-0.60 0.00
0.55 1.00
-2.12
0.12
1.00
0.59
2.72
1.80
-0.15
0.86
15.16 0.36
0.41
38,51,287.00 1.43
1.51
-1.81
0.16
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.69 0.25 1.28 Excluded from multivariate logistic analysis
0.01ab
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.61
0.45
0.99
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.28
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.08
0.32
Excluded from multivariate logistic analysis Excluded from multivariate logistic analysis
0.02ab
Excluded from multivariate logistic analysis
0.11
\0.001ab
Excluded from multivariate logistic analysis
Coefficient estimates
P value
Odds ratio
P value
Coefficient estimates
Multivariate logistic analysis
Univariate logistic analysis
Gestational age
Gender
Covariates
Table 1 Univariate and multivariate analysis of maternal and natal covariates for ROP development in ELWB
0.38
0.04
0.36
0.52
0.00
0.64
0.91
0.55
0.02
0.99
0.35
4.40
0.62
5.68
4.46
NA
1.14
8.50
5.96
0.61
1.00
0.80
95 % confidence interval
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4.52
1.00 1.00
Excluded from multivariate logistic analysis
1.00 1.00
Excluded from multivariate logistic analysis
0.00 0.15 -1.87
1.00 1.00
Excluded from multivariate logistic analysis
0.32 1.00 1.00
Coefficient estimates P value 95 % confidence interval
Multivariate logistic analysis
Odds ratio
95 % confidence interval
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Odds ratio
1.00
1.00
1.00
1.00
Coefficient estimates
0.00
0.00
0.00
0.00
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•
Statistically significant b
a
Clinically significant
\0.001b Meningitis
\0.001b
\0.001b Hypoglycemia
Sepsis
\0.001b
•
Total parenteral nutrition
P value
Covariates
Table 1 continued
Univariate logistic analysis
Fig. 1 Schematic diagram of the distribution of ELBW infants
Postnatal interventions: surfactant administration; mechanical ventilation; use of supplementary oxygen; maintenance supplementary oxygen concentration (mean oxygen concentration); use of non-steroidal anti-inflammatory agents (NSAID) for patent ductus arteriosus (PDA) closure; blood transfusion; and total parental nutrition (TPN). Neonatal diseases: respiratory distress syndrome (RDS); bronchopulmonary dysplasia; hypotension; congenital heart disease; PDA; anemia (defined as hemoglobin \110 g/l, hematocrit \25 %); thrombocytopenia; neonatal jaundice (NNJ), phototherapy, and intraventricular hemorrhage (IVH); necrotizing enterocolitis (NEC); hypoglycemia; sepsis (culture positive or use antibiotics for more than 7 days); and meningitis.
Statistics To eliminate the duplication of data from multiple pregnancies, only 1 subject in cases of multiple
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pregnancies was randomized (by card shuffling) for inclusion in the statistical analysis. The correlation of the 34 covariates with the development of ROP and Type 1 ROP was analyzed separately using univariate and multiple logistic regression analyses. Univariate correlation between the covariates and ROP development was analyzed using logistic regression and linear regression for categorical and continuous variables, respectively. For multiple logistic regressions, covariates with zero estimate of coefficients were excluded. Variable selection by elastic net method was used to select out redundant covariates to address the high collinearity of the sample. Correlations were expressed in coefficients and odds ratio (OR) and a P value less than 0.05 was considered as statistically significant. All means were expressed as mean ± standard deviation.
Results During the study period, a total of 612 preterm infants were screened. Out of the 612 screened infants, 152 (24.8 %) met the inclusion criteria of ELBW with BW B1,000 g. Of those infants, 1 (0.7 %) did not survive before completion of ROP screening and 2 (1.3 %) had insufficient clinical information; these 3 (2.0 %) cases were excluded. Thirty-six infants belonged to multiple pregnancies and 1 infant from each multiple pregnancies was randomized for inclusion in the study. The remaining 131 eligible, ELBW, preterm infants were included for regression analysis. (Fig. 1). Demographics Of the 131 infants included in the study, all were of Chinese ethnicity. There were 83 male (63.4 %) and 48 female (36.6 %) subjects. The mean GA at birth was 27.3 ± 3.3 weeks (range of 24.0–38.3 weeks) and the mean BW was 806.9 ± 133.7 g (range 445–1,000 g). The majority (113/131) was singletons (86.3 %), 17 were twins (13.0 %), and 1 was triplets (0.8 %). ROP of any stage developed in 70 infants (53.4 %) and Type 1 ROP developed in 19 infants (14.5 %).
lighter BW; vaginal delivery; postnatal hypotension; inotropes use; RDS, bronchopulmonary dysplasia; surfactant use; invasive mechanical ventilation; and supplementary oxygen (all P B 0.01) (Table 1). The following covariates were also significantly associated with ROP on a statistical level (all P B 0.01) but as the OR = 1.00, there was no clinical significance in these covariates as predictors of ROP: higher mean oxygen concentration; congenital heart disease; the presence of PDA; NSAID use; anemia; thrombocytopenia; blood transfusion; IVH; NEC; NNJ; phototherapy; TPN; hypoglycemia; sepsis; and meningitis (Table 1). Using multivariate analysis, the significant protective factor for ROP development included the presence of PET (P = 0.02) and congenital heart disease in the neonate (P = 0.01) (Table 1). Using multivariate logistic analysis, only a smaller GA and the presence of congenital heart disease were significant risk factors for ROP development (P \ 0.01), while the presence of PET was the only protective factor (P = 0.02) (Table 1). Risk factors analysis for Type 1 ROP For Type 1 ROP using univariate analysis, the following were significant risk factors: a smaller GA; lighter BW; surfactant use; and invasive mechanical ventilation (P B 0.02) (Table 2). The following covariates were also significantly associated with Type 1 ROP on a statistical level (all P B 0.01) but as the OR = 1.00, there was no clinical significance of these covariates as predictors of ROP: oxygen supplement; higher mean oxygen concentration; congenital heart disease; the presence of PDA; NSAID use; anemia; thrombocytopenia; blood transfusion; IVH; NEC; NNJ; phototherapy; TPN; hypoglycemia; sepsis; and meningitis. The only protective factor for Type 1 ROP development was the presence of PET (P = 0.02) (Table 2). For Type 1 ROP, none of the covariates reached a level of statistical significance using multivariate analysis (Table 2).
Risk factors analysis for ROP
Discussion
Using univariate analysis, the following were significant risk factors for ROP development: smaller GA;
ELBW infants, in general, have greater systemic morbidities among preterm neonates and have high
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123 0.76 0.38 0.16 0.05
Apgar score 5 min
Apgar score 10 min
Respiratory distress syndrome
Bronchopulmonary dysplasia
0.00 0.00 0.00
\0.001b \0.001b \0.001b
Mean oxygen concentration, FiO2 (%)
Congenital heart disease
Patent ductus arteriosus 0.00 0.00 0.00 0.00 0.00 0.00 0.00
\0.001 \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b
NSAID use
Anemia
Thrombocytopenia
Blood transfusion Intraventricular hemorrhage
Necrotizing colitis
Neonatal janice
Phototherapy
0.00
NA
\0.001b
Oxygen supplement
b
17.08
1.84
0.97
15.85
-0.15
-0.04
-0.03 -0.14
\0.001ab
0.02
0.57 0.65
Invasive mechanical ventilation
Surfactant use
0.96 0.25
Antenatal steroid use Apgar score 1 min
b
0.25 0.19
Postnatal hypotension
Inotropes use
0.21
1.03
0.19 0.67
0.13
Gestational diabetes mellitus
In-vitro fertilization
-1.84 -15.86
0.02b
Pre-eclampsia
Delivery (Caesarian vs. vaginal)
1.09
-0.01
-1.43
0.05
\0.001ab
-0.56
Coefficient estimates
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
NA
26158660.00
6.29
2.65
7625957.00
0.86
0.96
0.97 0.87
1.92
1.77
1.24
2.81
0.00
0.16
2.98
0.99
0.24
0.57
Odds ratio
Multivariate logistic analysis
Multiple pregnancies
\0.001
ab
Birth weight
0.30
P value
Gestational age
Gender
Covariates
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.00
1.21
0.99
0.00
0.62
0.77
0.32 0.68
0.72
0.67
0.46
0.56
NA
0.01
0.99
0.99
0.11
0.18
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
NA
115.63
7.61
NA
1.23
1.24
3.65 1.11
5.22
4.89
3.34
11.31
1.57E ? 51
0.82
8.54
1.00
0.43
1.62
95 % confidence interval
84.99
-143.07
50.20
110.29
-125.70
17.26
57.94
-0.22
-5.73
-30.93
Coefficient estimates
8.10E ? 36
0.00
6.30E ? 21
7.94E ? 47
0.00
3.13E ? 07
1.45E ? 25
0.80
0.00
0.00
Odds ratio
-16.68
0.00
107.03
3.02E ? 46
174.66 -96.13
-72.81
-88.39
111.94
9.06
-43.81
7.15E ? 75 0.00
0.00
0.00
4.13E ? 48
8621.46
0.00
NA
1.00
NA
-31.84
NA
0.00
Excluded from multivariate logistic analysis
1.00 1.00
1.00
1.00
1.00
1.00
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis Excluded from multivariate logistic analysis
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
P value
Table 2 Univariate and multivariate analysis of maternal and natal covariates for Type 1 ROP development in ELWB
NA
0.00
0.00 0.00
0.00
0.00
0.00
0.00
NA
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
NA
Infinity
NA Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
252289.80
Infinity
Infinity
95 % confidence interval
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Infinity Clinically significant
Statistically significant b
a
Infinity 0.00
0.00 1.16E ? 77
9.08E ? 60 140.36
177.44 1.00
1.00 1.00
1.00 1.00
1.00 1.00
1.00 0.00
0.00 \0.001
\0.001b
Sepsis
Meningitis
Infinity
Infinity
0.00 \0.001b Hypoglycemia
b
0.00
0.00 2.22E ? 47
22,74,388.00 14.64
109.02 1.00
1.00 1.00
1.00 1.00 0.00 \0.001b Total parenteral nutrition
1.00
95 % confidence interval Odds ratio Coefficient estimates
1.00
Odds ratio Coefficient estimates P value Multivariate logistic analysis P value Covariates
Table 2 continued
1.00
95 % confidence interval
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risk of death [11, 12]. ROP is one of these wellrecognized morbidities and in many developed countries with advanced perinatal and neonatal intensive care support, ROP is primarily confined the ELBW infant population [13, 14]. The incidence of ROP in any stage, among ELBW infants, varies in different countries with reported ranges from 24.4 to 86.7 % [15–18], while our study showed an incidence of 53.4 % in ELBW Chinese among those meeting the criteria for ROP screening based on the Royal College of Ophthalmologists ROP guideline. Our findings were consistent with a Malaysian study by Choo et al. that reported an incidence of 58.6 % [17]. While in the Brunei Darussalam study, the ROP incidence among ELBW was as high as 86.7 % [18]. The incidence of Type 1 ROP among the ELBW infants in our study was 14.5 %, which is similar to the reported incidence in Brazil (12.7 %) by Fortes et al. [19] but lower than that reported in a Taiwanese population (29.3 %) [20]. Martı´nez-Cruz et al. found that multiple gestations in ELBW infants were associated with a higher risk of ROP development [15]. We did not find any statistically significant association between ROP and multiple gestations. Likewise, they showed that the presence of PET was associated with development of ROP; however, we demonstrated that PET was a protective factor for both the development of ROP and Type 1 ROP (OR = 0.12, P = 0.02 for ROP in multivariate analysis and OR = 0.16, P = 0.02 for Type 1 ROP in univariate analysis). Xiao et al. have offered a hypothesis for the protective effects of PET on ROP through the transcorneal absorption of antiangiogenic factors in the amniotic fluid which is elevated in women with PET [21]. It is interesting to note that while BW was an independent risk factor for ROP and Type 1 ROP on univariate analysis (both P \ 0.001), it was no longer a statistically significant risk factor on multivariate analysis in both diseases. Our analysis revealed that neonatal congenital heart disease was a significant protective factor for ROP on multivariate analysis (OR = 0.16, P = 0.01) which is in contrast to previous reports in the literature [22–24]. John et al. [22] and Kalina et al. [23] reported a positive association with ROP and cyanotic heart disease. Polito et al. [24] revealed that the higher risk of ROP in congenital heart disease may be partly attributed to systemic infections. The majority of
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congenital heart disease in our population were noncyanotic (13/16, 81.3 %). We postulate that in those with congenital heart disease, more vigilant monitoring and control of oxygen may have offered a better optimization of the target oxygen saturation, conferring an indirect protective mechanism for ROP development. Englert et al. [25] reported a significant association between the severity of ROP and the number of blood transfusion (P = 0.04) among ELBW infants. In our study, while anemia and blood transfusion were significantly associated with ROP and Type 1 ROP (P \ 0.001) on a statistical level, there was no clinical significance as the OR = 1.00. We noted that vaginal delivery was a significant independent risk factor for ROP to develop in ELBW infants (OR = 3.26, P \ 0.001). This was in agreement with Manzoni et al. [26], who reported that vaginal delivery was a significant independent factor for the development of threshold ROP when compared to Cesarean section delivery in univariate analysis (P = 0.008) and multivariate logistic regression (P = 0.04). In contrast, Shah et al. [27] found that Cesarean section delivery was significantly associated with the occurrence of ROP. Only limited information exists in the literature on the incidence and risk factors of ELBW Chinese infants. With economic growth as well as the increasing standard of medical care throughout Chinese populations in Mainland China, it is expected that the survival rate of ELBW will continue to increase in the coming years and knowledge on the risk factors of ROP development in this particular vulnerable population is important in preventing ophthalmic morbidities. To the best of our knowledge, it is one of few studies reporting the incidence and risk factors of ROP and Type 1 ROP in an ELBW Chinese population using internationally recognized ROP screening guidelines. Our study had its limitations. Firstly, the retrospective nature of this study inventible generates inconsistencies in data, although every effort was made to exclude subjects with incomplete clinical data. Secondly, subjects were screened by 3 pediatric ophthalmologists and minor inter-observer variability can exists but as all were trained to follow a strict ROP screening guideline and given the large population requiring screening, it was the most optimal balance in terms of providing clinical service and standardization for research. Nevertheless, this study provides
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important data on the incidence and risk factors of ROP in the ELBW Chinese population using more updated and stricter ROP screening guidelines than what currently exists in the literature. This serves as a platform for future multicentre, prospective trials among Chinese populations.
Conclusion In ELBW, preterm Chinese infants, a smaller GA, lighter BW, and the presence of congenital heart disease were significant risk factors for ROP development, while PET was protective in multivariate analysis.
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Int Ophthalmol 10. International Committee for the Classification of Retinopathy of Prematurity (2005) The international classification of retinopathy of prematurity revisited. Arch Ophthalmol 123(7):991–999 11. Valcamonico A, Accorsi P, Sanzeni C, Martelli P, La Boria P, Cavazza A, Frusca T (2007) Mid- and long-term outcome of extremely low birth weight (ELBW) infants: an analysis of prognostic factors. J Matern Fetal Neonatal Med 20(6):465–471 12. Tommiska V, Heinonen K, Ikonen S, Kero P, Pokela M-L, Renlund M, Virtanen M, Fellman V (2001) A national shortterm follow-up study of extremely low birth weight infants born in Finland in 1996–1997. Pediatrics 107:e2. doi:10. 1542/peds.107.1.e2 13. Fielder AR, Reynolds JD (2001) Retinopathy of prematurity: clinical aspects. Semin Neonatol 6:461–475 14. Spencer Rand (2006) Long-term visual outcomes in extremely low-birth-weight children (an American ophthalmological society thesis). Trans Am Ophthalmol Soc 104:493–516 15. Martı´nez-Cruz CF, Salgado-Valladares M, Poblano A, Trinidad-Pe´rez MC (2012) Risk factors associated with retinopathy of prematurity and visual alterations in infants with extremely low birth weight. Rev Invest Clin 64(2):136–143 16. Fortes Filho JB, Eckert GU, Procianoy L, Barros CK, Procianoy RS (2009) 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 (Lond) 23(1):25–30 17. Choo MM, Martin FJ, Theam LC, U-Teng C (2009) Retinopathy of prematurity in extremely low birth weight infants in Malaysia. J AAPOS 13(5):446–449 18. Ali Nadir Ali Mohamed, George Joshua, Joshi Nayan, Chong Elizabeth (2013) Prevalence of retinopathy of
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ORIGINAL PAPER
Incidence and risk factors for retinopathy of prematurity in extreme low birth weight Chinese infants Gordon S. K. Yau • Jacky W. Y. Lee • Victor T. Y. Tam • Catherine C. L. Liu Benjamin C. Y. Chu • Can Y. F. Yuen
•
Received: 20 April 2014 / Accepted: 20 May 2014 Springer Science+Business Media Dordrecht 2014
Abstract The objective of this study is to determine the incidence and risk factors of retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) Chinese infants. A retrospective medical record review of all ELBW (B1,000 g) neonates screened for ROP from 2007 to 2012 was performed in Hong Kong. ROP screening was conducted at 2 neonatal intensive care units by 3 pediatric ophthalmologists using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. In 131 ELBW Chinese infants, the mean gestational age (GA) and birth weight (BW) were 27.3 ± 3.3 weeks and 806.9 ± 133.7 g, respectively. The incidence of ROP and Type 1 ROP was 53.4 and 14.5 %, respectively. For ROP, a lighter BW, smaller GA, vaginal delivery, postnatal hypotension, inotrope use, bronchopulmonary dysplasia, surfactant use, invasive
mechanical ventilation, and supplementary oxygen were independent risk factors for ROP, while PET was protective (P B 0.02). On multivariate analysis, a smaller GA was a risk factor, while PET and congenital heart disease were protective for ROP development (P B 0.01). For Type 1 ROP, a lighter BW, smaller GA, surfactant use, and invasive mechanical ventilation were independent risk factors for ROP, while PET was protective (P B 0.02). There were no significant covariates on multivariate analysis for Type 1 ROP. In ELBW, preterm Chinese infants, a smaller GA was a risk factor for ROP, while PET and congenital heart disease were protective for ROP development in multivariate analysis. Keywords Retinopathy of prematurity ROP Extreme low birth weight Chinese Risk factors
Introduction G. S. K. Yau (&) J. W. Y. Lee V. T. Y. Tam B. C. Y. Chu C. Y. F. Yuen The Department of Ophthalmology, Caritas Medical Centre, 111 Wing Hong Street, Kowloon, Hong Kong SAR, People’s Republic of China e-mail: [email protected] C. C. L. Liu Department of Applied Mathematics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, People’s Republic of China
Retinopathy of prematurity (ROP) is a vasoproliferative disease targeting the developing retina particularly in those with low birth weight and preterm gestation [1]. ROP is one of the leading causes of childhood blindness in developed nations [2]. It is no longer uncommon for extremely low birth weight (ELBW, B1,000 g) neonates to survive following the advances in neonatal intensive unit care over the past decades [3–5], thus, understanding the
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Treatment for Retinopathy of Prematurity (ETROP) study [9]. The staging of ROP was recorded according to the revised International Classification of ROP, including the extent, zone, and the presence or absence of ‘‘plus’’ disease [10]. Type 1 ROP was defined as high risk prethreshold ROP, with either one of the following features: (i) Zone I, any stage ROP with plus disease (C2 quadrant involvement as per the ETROP Study); (ii) Zone I, stage 3 ROP with or without plus disease; or (iii) Zone II, stage 2 or 3 ROP with plus disease [9].
determinants of ROP development in this particular group of ELBW neonates is clinically relevant. While Hong Kong has a comparable standard of medical care to its Western counterparts [6], there is a paucity of data in the literature reporting the incidence and associations of ROP among ELWB Chinese infants using newer international guidelines such as the Royal College of Ophthalmologists and United Kingdom (UK)-ROP Guidelines [7, 8]. The aim of this study was to analyze occurrence and associations of ROP among ELBW preterm infants in the Chinese population.
Patients and methods The study was approved by the Institutional Review Board of the Hospital Authority of Hong Kong. The study was conducted in accordance with the Declaration of Helsinki, and no patient personal data were disclosed in the study. The authors declare no financial or proprietary interests. This was a retrospective study conducted at Caritas Medical Centre, Hong Kong Special Administrative Region, China, which provides ophthalmological service to 2 neonatal intensive care units (NICU) for a population of 1.8 million. Medical records for consecutive subjects screened for ROP between the period of January 2007 and December 2012 were retrieved using the Clinical Data Record System of the Hospital Authority of Hong Kong. ROP screening criterion •
All preterm babies admitted to these 2 NICU’s with a birth weight (BW) B1,500 g and/or gestational age (GA) B32 weeks were referred to a pediatric ophthalmologist for evaluation. All eligible preterms were examined according to the screening protocol recommended by the Royal College of Ophthalmologists and UK-ROP) guidelines [9, 10]. Subjects were first screened at 4–8 weeks of postnatal age (C30 week GA) and were examined weekly to bi-weekly, until retinal vascularisation reached zone 3 or feature of established ROP regression [9]. Treatment was diode laser which was implemented when the disease progressed to Type 1 ROP as per the Early
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All examinations were performed by three experienced pediatric ophthalmologists (SKY, TYT, CYC). Each infant was screened by an indirect ophthalmoscope using a 30-diopter lens after full pharmacological pupil dilatation with tropicamide 0.5 % and phenylephrine 1 % eye drops. A lid speculum with scleral indentation after topical anesthesia (amethocaine) was routinely used. All screenings were performed under oxygen saturation monitoring and the screening was temporarily withheld in case of desaturations. The inclusion criteria included all subjects with BW B1,000 g (ELBW) that underwent ROP screening. Neonates with incomplete clinical data or those that were diseased before the completion of ROP screening were excluded. The primary outcome measures included: the severity of ROP (the extent, zone, and the presence or absence of ‘‘plus’’ disease) as well as the 34 risk factors (both maternal and neonatal) for the development of ROP as follows: Antenatal maternal risk factors: (Table 1) •
• • •
Maternal diseases: pre-eclampsia (PET), gestational diabetes mellitus (GDM), order of pregnancy (singleton or multiple gestations). In-vitro fertilization (IVF). Use of antenatal steroid (ANS). Mode of delivery (Cesarean section versus vaginal delivery).
Neonatal risk factors: (Table 1) • •
Demographic information (GA, BW, gender); Apgar Scores at 1, 5, and 10 min;
1.18 1.28 0.89
\0.001ab \0.001ab 0.01ab 0.85 0.09 0.69
Delivery (Caesarian vs. vaginal)
Postnatal hypotension
Inotropes use
Antenatal steroid use
Apgar score 1 min
Apgar score 5 min
Apgar score 10 min
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
\0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b
Oxygen supplement
Mean oxygen concentration, FiO2 (%)
Congenital heart disease
Patent ductus arteriosus NSAID use
Anemia
Thrombocytopenia
Blood transfusion
Intraventricular hemorrhage 0.00 0.00
\0.001 \0.001b \0.001b
Necrotizing colitis
Neonatal janice
Phototherapy
0.00
NA
\0.001ab
Invasive mechanical ventilation
b
1.55
\0.001
Surfactant use 1.70
0.91
0.01ab
Bronchopulmonary dysplasia ab
-0.06 16.81
0.64 \0.001ab
Respiratory distress syndrome
-0.03
-0.15
0.08
-0.45 -0.15
–0.03 -1.93
0.94 0.56 0.82
Gestational diabetes mellitus In-vitro fertilization
Pre-eclampsia
\0.001ab
-0.01
\0.001ab
Birth weight
Multiple pregnancies
-0.22 -0.85
0.55 \0.001ab
0.80
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
NA
4.73
5.45
2.48
19919910.00
0.94
0.97
0.86
1.08
2.44
3.58
3.26
0.64 0.86
0.14
0.97
0.99
0.43
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.92
2.23
1.22
0.00
0.71
0.81
0.71
0.46
1.19
1.75
1.61
0.12 0.23
0.05
0.38
0.99
0.31
0.39
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
12.93
14.85
5.15
NA
1.22
1.15
1.02
2.54
5.15
7.56
6.81
3.01 3.24
0.37
2.48
1.00
0.56
1.64
95 % confidence interval
Odds ratio
-0.60 0.00
0.55 1.00
-2.12
0.12
1.00
0.59
2.72
1.80
-0.15
0.86
15.16 0.36
0.41
38,51,287.00 1.43
1.51
-1.81
0.16
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.69 0.25 1.28 Excluded from multivariate logistic analysis
0.01ab
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.61
0.45
0.99
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.28
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
0.08
0.32
Excluded from multivariate logistic analysis Excluded from multivariate logistic analysis
0.02ab
Excluded from multivariate logistic analysis
0.11
\0.001ab
Excluded from multivariate logistic analysis
Coefficient estimates
P value
Odds ratio
P value
Coefficient estimates
Multivariate logistic analysis
Univariate logistic analysis
Gestational age
Gender
Covariates
Table 1 Univariate and multivariate analysis of maternal and natal covariates for ROP development in ELWB
0.38
0.04
0.36
0.52
0.00
0.64
0.91
0.55
0.02
0.99
0.35
4.40
0.62
5.68
4.46
NA
1.14
8.50
5.96
0.61
1.00
0.80
95 % confidence interval
Int Ophthalmol
123
4.52
1.00 1.00
Excluded from multivariate logistic analysis
1.00 1.00
Excluded from multivariate logistic analysis
0.00 0.15 -1.87
1.00 1.00
Excluded from multivariate logistic analysis
0.32 1.00 1.00
Coefficient estimates P value 95 % confidence interval
Multivariate logistic analysis
Odds ratio
95 % confidence interval
Int Ophthalmol
Odds ratio
1.00
1.00
1.00
1.00
Coefficient estimates
0.00
0.00
0.00
0.00
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•
Statistically significant b
a
Clinically significant
\0.001b Meningitis
\0.001b
\0.001b Hypoglycemia
Sepsis
\0.001b
•
Total parenteral nutrition
P value
Covariates
Table 1 continued
Univariate logistic analysis
Fig. 1 Schematic diagram of the distribution of ELBW infants
Postnatal interventions: surfactant administration; mechanical ventilation; use of supplementary oxygen; maintenance supplementary oxygen concentration (mean oxygen concentration); use of non-steroidal anti-inflammatory agents (NSAID) for patent ductus arteriosus (PDA) closure; blood transfusion; and total parental nutrition (TPN). Neonatal diseases: respiratory distress syndrome (RDS); bronchopulmonary dysplasia; hypotension; congenital heart disease; PDA; anemia (defined as hemoglobin \110 g/l, hematocrit \25 %); thrombocytopenia; neonatal jaundice (NNJ), phototherapy, and intraventricular hemorrhage (IVH); necrotizing enterocolitis (NEC); hypoglycemia; sepsis (culture positive or use antibiotics for more than 7 days); and meningitis.
Statistics To eliminate the duplication of data from multiple pregnancies, only 1 subject in cases of multiple
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pregnancies was randomized (by card shuffling) for inclusion in the statistical analysis. The correlation of the 34 covariates with the development of ROP and Type 1 ROP was analyzed separately using univariate and multiple logistic regression analyses. Univariate correlation between the covariates and ROP development was analyzed using logistic regression and linear regression for categorical and continuous variables, respectively. For multiple logistic regressions, covariates with zero estimate of coefficients were excluded. Variable selection by elastic net method was used to select out redundant covariates to address the high collinearity of the sample. Correlations were expressed in coefficients and odds ratio (OR) and a P value less than 0.05 was considered as statistically significant. All means were expressed as mean ± standard deviation.
Results During the study period, a total of 612 preterm infants were screened. Out of the 612 screened infants, 152 (24.8 %) met the inclusion criteria of ELBW with BW B1,000 g. Of those infants, 1 (0.7 %) did not survive before completion of ROP screening and 2 (1.3 %) had insufficient clinical information; these 3 (2.0 %) cases were excluded. Thirty-six infants belonged to multiple pregnancies and 1 infant from each multiple pregnancies was randomized for inclusion in the study. The remaining 131 eligible, ELBW, preterm infants were included for regression analysis. (Fig. 1). Demographics Of the 131 infants included in the study, all were of Chinese ethnicity. There were 83 male (63.4 %) and 48 female (36.6 %) subjects. The mean GA at birth was 27.3 ± 3.3 weeks (range of 24.0–38.3 weeks) and the mean BW was 806.9 ± 133.7 g (range 445–1,000 g). The majority (113/131) was singletons (86.3 %), 17 were twins (13.0 %), and 1 was triplets (0.8 %). ROP of any stage developed in 70 infants (53.4 %) and Type 1 ROP developed in 19 infants (14.5 %).
lighter BW; vaginal delivery; postnatal hypotension; inotropes use; RDS, bronchopulmonary dysplasia; surfactant use; invasive mechanical ventilation; and supplementary oxygen (all P B 0.01) (Table 1). The following covariates were also significantly associated with ROP on a statistical level (all P B 0.01) but as the OR = 1.00, there was no clinical significance in these covariates as predictors of ROP: higher mean oxygen concentration; congenital heart disease; the presence of PDA; NSAID use; anemia; thrombocytopenia; blood transfusion; IVH; NEC; NNJ; phototherapy; TPN; hypoglycemia; sepsis; and meningitis (Table 1). Using multivariate analysis, the significant protective factor for ROP development included the presence of PET (P = 0.02) and congenital heart disease in the neonate (P = 0.01) (Table 1). Using multivariate logistic analysis, only a smaller GA and the presence of congenital heart disease were significant risk factors for ROP development (P \ 0.01), while the presence of PET was the only protective factor (P = 0.02) (Table 1). Risk factors analysis for Type 1 ROP For Type 1 ROP using univariate analysis, the following were significant risk factors: a smaller GA; lighter BW; surfactant use; and invasive mechanical ventilation (P B 0.02) (Table 2). The following covariates were also significantly associated with Type 1 ROP on a statistical level (all P B 0.01) but as the OR = 1.00, there was no clinical significance of these covariates as predictors of ROP: oxygen supplement; higher mean oxygen concentration; congenital heart disease; the presence of PDA; NSAID use; anemia; thrombocytopenia; blood transfusion; IVH; NEC; NNJ; phototherapy; TPN; hypoglycemia; sepsis; and meningitis. The only protective factor for Type 1 ROP development was the presence of PET (P = 0.02) (Table 2). For Type 1 ROP, none of the covariates reached a level of statistical significance using multivariate analysis (Table 2).
Risk factors analysis for ROP
Discussion
Using univariate analysis, the following were significant risk factors for ROP development: smaller GA;
ELBW infants, in general, have greater systemic morbidities among preterm neonates and have high
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123 0.76 0.38 0.16 0.05
Apgar score 5 min
Apgar score 10 min
Respiratory distress syndrome
Bronchopulmonary dysplasia
0.00 0.00 0.00
\0.001b \0.001b \0.001b
Mean oxygen concentration, FiO2 (%)
Congenital heart disease
Patent ductus arteriosus 0.00 0.00 0.00 0.00 0.00 0.00 0.00
\0.001 \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b \0.001b
NSAID use
Anemia
Thrombocytopenia
Blood transfusion Intraventricular hemorrhage
Necrotizing colitis
Neonatal janice
Phototherapy
0.00
NA
\0.001b
Oxygen supplement
b
17.08
1.84
0.97
15.85
-0.15
-0.04
-0.03 -0.14
\0.001ab
0.02
0.57 0.65
Invasive mechanical ventilation
Surfactant use
0.96 0.25
Antenatal steroid use Apgar score 1 min
b
0.25 0.19
Postnatal hypotension
Inotropes use
0.21
1.03
0.19 0.67
0.13
Gestational diabetes mellitus
In-vitro fertilization
-1.84 -15.86
0.02b
Pre-eclampsia
Delivery (Caesarian vs. vaginal)
1.09
-0.01
-1.43
0.05
\0.001ab
-0.56
Coefficient estimates
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
NA
26158660.00
6.29
2.65
7625957.00
0.86
0.96
0.97 0.87
1.92
1.77
1.24
2.81
0.00
0.16
2.98
0.99
0.24
0.57
Odds ratio
Multivariate logistic analysis
Multiple pregnancies
\0.001
ab
Birth weight
0.30
P value
Gestational age
Gender
Covariates
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.00
1.21
0.99
0.00
0.62
0.77
0.32 0.68
0.72
0.67
0.46
0.56
NA
0.01
0.99
0.99
0.11
0.18
1.00
1.00
1.00
1.00 1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
NA
115.63
7.61
NA
1.23
1.24
3.65 1.11
5.22
4.89
3.34
11.31
1.57E ? 51
0.82
8.54
1.00
0.43
1.62
95 % confidence interval
84.99
-143.07
50.20
110.29
-125.70
17.26
57.94
-0.22
-5.73
-30.93
Coefficient estimates
8.10E ? 36
0.00
6.30E ? 21
7.94E ? 47
0.00
3.13E ? 07
1.45E ? 25
0.80
0.00
0.00
Odds ratio
-16.68
0.00
107.03
3.02E ? 46
174.66 -96.13
-72.81
-88.39
111.94
9.06
-43.81
7.15E ? 75 0.00
0.00
0.00
4.13E ? 48
8621.46
0.00
NA
1.00
NA
-31.84
NA
0.00
Excluded from multivariate logistic analysis
1.00 1.00
1.00
1.00
1.00
1.00
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis
1.00
Excluded from multivariate logistic analysis
Excluded from multivariate logistic analysis Excluded from multivariate logistic analysis
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
P value
Table 2 Univariate and multivariate analysis of maternal and natal covariates for Type 1 ROP development in ELWB
NA
0.00
0.00 0.00
0.00
0.00
0.00
0.00
NA
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
NA
Infinity
NA Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
Infinity
252289.80
Infinity
Infinity
95 % confidence interval
Int Ophthalmol
Infinity Clinically significant
Statistically significant b
a
Infinity 0.00
0.00 1.16E ? 77
9.08E ? 60 140.36
177.44 1.00
1.00 1.00
1.00 1.00
1.00 1.00
1.00 0.00
0.00 \0.001
\0.001b
Sepsis
Meningitis
Infinity
Infinity
0.00 \0.001b Hypoglycemia
b
0.00
0.00 2.22E ? 47
22,74,388.00 14.64
109.02 1.00
1.00 1.00
1.00 1.00 0.00 \0.001b Total parenteral nutrition
1.00
95 % confidence interval Odds ratio Coefficient estimates
1.00
Odds ratio Coefficient estimates P value Multivariate logistic analysis P value Covariates
Table 2 continued
1.00
95 % confidence interval
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risk of death [11, 12]. ROP is one of these wellrecognized morbidities and in many developed countries with advanced perinatal and neonatal intensive care support, ROP is primarily confined the ELBW infant population [13, 14]. The incidence of ROP in any stage, among ELBW infants, varies in different countries with reported ranges from 24.4 to 86.7 % [15–18], while our study showed an incidence of 53.4 % in ELBW Chinese among those meeting the criteria for ROP screening based on the Royal College of Ophthalmologists ROP guideline. Our findings were consistent with a Malaysian study by Choo et al. that reported an incidence of 58.6 % [17]. While in the Brunei Darussalam study, the ROP incidence among ELBW was as high as 86.7 % [18]. The incidence of Type 1 ROP among the ELBW infants in our study was 14.5 %, which is similar to the reported incidence in Brazil (12.7 %) by Fortes et al. [19] but lower than that reported in a Taiwanese population (29.3 %) [20]. Martı´nez-Cruz et al. found that multiple gestations in ELBW infants were associated with a higher risk of ROP development [15]. We did not find any statistically significant association between ROP and multiple gestations. Likewise, they showed that the presence of PET was associated with development of ROP; however, we demonstrated that PET was a protective factor for both the development of ROP and Type 1 ROP (OR = 0.12, P = 0.02 for ROP in multivariate analysis and OR = 0.16, P = 0.02 for Type 1 ROP in univariate analysis). Xiao et al. have offered a hypothesis for the protective effects of PET on ROP through the transcorneal absorption of antiangiogenic factors in the amniotic fluid which is elevated in women with PET [21]. It is interesting to note that while BW was an independent risk factor for ROP and Type 1 ROP on univariate analysis (both P \ 0.001), it was no longer a statistically significant risk factor on multivariate analysis in both diseases. Our analysis revealed that neonatal congenital heart disease was a significant protective factor for ROP on multivariate analysis (OR = 0.16, P = 0.01) which is in contrast to previous reports in the literature [22–24]. John et al. [22] and Kalina et al. [23] reported a positive association with ROP and cyanotic heart disease. Polito et al. [24] revealed that the higher risk of ROP in congenital heart disease may be partly attributed to systemic infections. The majority of
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congenital heart disease in our population were noncyanotic (13/16, 81.3 %). We postulate that in those with congenital heart disease, more vigilant monitoring and control of oxygen may have offered a better optimization of the target oxygen saturation, conferring an indirect protective mechanism for ROP development. Englert et al. [25] reported a significant association between the severity of ROP and the number of blood transfusion (P = 0.04) among ELBW infants. In our study, while anemia and blood transfusion were significantly associated with ROP and Type 1 ROP (P \ 0.001) on a statistical level, there was no clinical significance as the OR = 1.00. We noted that vaginal delivery was a significant independent risk factor for ROP to develop in ELBW infants (OR = 3.26, P \ 0.001). This was in agreement with Manzoni et al. [26], who reported that vaginal delivery was a significant independent factor for the development of threshold ROP when compared to Cesarean section delivery in univariate analysis (P = 0.008) and multivariate logistic regression (P = 0.04). In contrast, Shah et al. [27] found that Cesarean section delivery was significantly associated with the occurrence of ROP. Only limited information exists in the literature on the incidence and risk factors of ELBW Chinese infants. With economic growth as well as the increasing standard of medical care throughout Chinese populations in Mainland China, it is expected that the survival rate of ELBW will continue to increase in the coming years and knowledge on the risk factors of ROP development in this particular vulnerable population is important in preventing ophthalmic morbidities. To the best of our knowledge, it is one of few studies reporting the incidence and risk factors of ROP and Type 1 ROP in an ELBW Chinese population using internationally recognized ROP screening guidelines. Our study had its limitations. Firstly, the retrospective nature of this study inventible generates inconsistencies in data, although every effort was made to exclude subjects with incomplete clinical data. Secondly, subjects were screened by 3 pediatric ophthalmologists and minor inter-observer variability can exists but as all were trained to follow a strict ROP screening guideline and given the large population requiring screening, it was the most optimal balance in terms of providing clinical service and standardization for research. Nevertheless, this study provides
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important data on the incidence and risk factors of ROP in the ELBW Chinese population using more updated and stricter ROP screening guidelines than what currently exists in the literature. This serves as a platform for future multicentre, prospective trials among Chinese populations.
Conclusion In ELBW, preterm Chinese infants, a smaller GA, lighter BW, and the presence of congenital heart disease were significant risk factors for ROP development, while PET was protective in multivariate analysis.
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