Search results and characteristics
This review included all of the eligible studies that were published as of May 29, 2021, and unpublished studies were not involved. A total of 3,868 articles were retrieved, and 22 and 30 articles describing ROP prevalence and ROP risk factors, respectively, that met the criteria were finally included (Fig. 1). Among the 22 studies describing the prevalence of ROP, there were 6 high-quality studies, 15 medium-quality studies and only one low-quality study. Among the 30 studies included in the analysis of ROP risk factors, data extracted from 28 studies could be meta-analyzed. 24 of these studies were of high-quality.
Prevalence of ROP
We extracted and merged data with a sample size of 30,118 from 22 studies7-28 and concluded that the prevalence of ROP in mainland China was 9.284% (95% CI: 6.546-12.022%). The highest prevalence was 20.34% (95% CI: 10.07-30.61%), which was reported in Jiang YR (1994)7, and the lowest prevalence was 1.10% (95% CI: 0.53-1.68%), which was mentioned in Tian N (2014)20 (Fig. 2).
The prevalence of boys and girls for ROP was 12.063% (95% CI: 8.225-15.902%) and 10.603% (95% CI: 5.811-15.395%), respectively (Table 1).
Table 1. Prevalence of ROP based on GA, BW, year, region and gender of studies
|
Variable
|
Studies(N)
|
Sample(N)
|
Heterogeneity
|
Prevalence(%)
|
95% CI
|
Total
|
Cases
|
I2
|
P-value
|
|
|
GA
|
<30w
|
6
|
253
|
102
|
96.40%
|
0.000
|
44.541
|
17.808-71.275
|
|
30-34w
|
6
|
900
|
131
|
94.30%
|
0.000
|
17.344
|
8.335-26.352
|
|
>34w
|
6
|
1550
|
60
|
89.30%
|
0.000
|
3.207
|
0.962-5.451
|
|
≤32w
|
8
|
8623
|
1889
|
91.40%
|
0.000
|
27.609
|
20.99-34.228
|
|
>32w
|
8
|
13802
|
1092
|
96.40%
|
0.000
|
8.369
|
5.11-11.629
|
BW
|
<1,000g
|
3
|
103
|
51
|
94.00%
|
0.000
|
42.470
|
3.616-81.324
|
|
<1,500g
|
12
|
10282
|
2438
|
94.50%
|
0.000
|
37.866
|
28.214-47.519
|
|
1,500-2,000g
|
10
|
1632
|
230
|
94.50%
|
0.000
|
16.444
|
10.205-22.682
|
|
>2,000g
|
10
|
2783
|
128
|
91.40%
|
0.000
|
4.503
|
2.537-6.469
|
|
2,000-2,500g
|
6
|
1824
|
87
|
93.00%
|
0.000
|
4.270
|
1.778-6.762
|
|
>2,500g
|
2
|
380
|
14
|
90.50%
|
0.001
|
3.298
|
-2.51-9.106
|
Year
|
2014-2018
|
9
|
4485
|
356
|
94.90%
|
0.000
|
7.725
|
4.742-10.707
|
|
1990-2013
|
12
|
25025
|
3037
|
99.20%
|
0.000
|
10.552
|
6.346-14.759
|
Region
|
Southern
|
12
|
26057
|
3117
|
99.30%
|
0.000
|
8.962
|
4.989-12.936
|
|
Northern
|
10
|
4061
|
326
|
86.50%
|
0.000
|
8.782
|
6.418-11.146
|
|
Eastern
|
14
|
66846
|
7371
|
95.90%
|
0.000
|
9.112
|
6.526-11.699
|
|
Western
|
3
|
2105
|
88
|
94.90%
|
0.000
|
4.339
|
0.822-7.855
|
|
Central
|
5
|
21403
|
2870
|
84.30%
|
0.000
|
12.083
|
9.838-14.328
|
Gender
|
Male
|
7
|
12379
|
1590
|
93.90%
|
0.000
|
12.063
|
8.225-15.902
|
|
Female
|
6
|
9722
|
1271
|
96.10%
|
0.000
|
10.603
|
5.811-15.395
|
Premature infants
|
6
|
2980
|
306
|
97.60%
|
0.000
|
11.556
|
5.422-17.691
|
Full-term infants with low birth-weight
|
2
|
298
|
2
|
0.00%
|
0.506
|
1.071
|
-0.591-2.732
|
N, number; CI, confidence interval; GA, gestational age; BW, birth weight; Premature infants, infants with gestational age less than 37 weeks; Full-term infants with low birth-weight, infants whose gestational age over 37 weeks but whose birth weight less than 2,500 grams.
Sensitivity analysis for prevalence
A sensitivity analysis of the prevalence of ROP (Fig. 3) showed that the exclusion of each study one by one did not have a significant impact on the overall combined results, thus suggesting good stability of the results. The cumulative meta-analysis of ROP prevalence sorted by publication year is shown in Fig. 3.
Subgroup analysis of ROP prevalence based on geographic region
We conducted a subgroup analysis of the prevalence of ROP in eastern, western and central China based on the survey area of each study. The results showed that the prevalence of ROP was the highest in central China at 12.083% (95% CI: 9.838-14.328%), whereas the prevalence of ROP in western China was the lowest at 4.339% (95% CI: 0.822-7.855%). The prevalence of ROP in central China was observed to be located the two previous prevalences at 9.112% (95% CI: 6.526-11.699%). However, there was no significant difference in the prevalence between South and North China (Table 1).
The prevalence of ROP based on gestational age
When grouped by gestational age, the combined results of ROP prevalence are shown in Table 1. In newborns with a gestational age of less than 30 weeks, the prevalence of ROP was as high as 44.541% (95% CI: 17.808-71.275%), which was only 3.207% (95% CI: 0.962-5.451%) in newborns with a gestational age of more than 34 weeks. With the increase of gestational age, the prevalence of ROP showed a downward trend.
The prevalence of ROP based on birth weight
The prevalence of ROP (as calculated by birth weight grouping) is shown in Table 1. According to the data of 3 included studies, the prevalence of ROP in infants with BW<1,000 g was up to 42.470% (95% CI: 3.616-81.324%). Ten studies reported the prevalence of ROP in infants with BW>2,000 g, which was only 4.503% (95% CI: 2.537-6.469%). The prevalence of ROP in infants with BW<1,500 g, BW between 1,500 and 2,000 g, BW between 2,000 and 2,500 g and BW>2,500 g was 37.866% (95% CI: 28.214-47.519%), 16.444% (95% CI: 10.205-22.682%), 4.270% (95% CI: 1.778-6.762%) and 3.298% (95% CI: -2.510-9.106%), respectively. The prevalence exhibited a significant downward trend with increasing birth weight.
Meta regression
The meta-regression analysis of ROP prevalence is shown in Fig. 4. The regression model showed that the prevalence of ROP decreased with increasing publication year, and the relationship was significantly different (meta-regression coefficient: -0.600, 95% CI: -1.152 to -0.0487, p=0.034). However, the variation between the studies was relatively large (Tau2=28.37), the 98.75% residual variation could be explained by the heterogeneity (I2=98.75%) and the covariate that was included in the model (the year of publication) could only be responsible for 14.5% of the total variation (Adj R-squared= 14.5%).
Publication bias
A funnel chart was used to test for publication bias (Fig. 5), and the Egger’s test results (t=0.46, p=0.652) showed that the funnel chart was symmetrical, thus suggesting that the possibility of publication bias in this study was unlikely.
Meta-analysis of risk factors for ROP
The meta-analysis of the univariate analysis of 50 risk factors for ROP in the Chinese population is shown in Table 2.
Table 2. Meta-analysis for risk factors of ROP in China
|
Variable
|
Studies (N)
|
Sample(N)
|
Heterogeneity
|
Model
|
ES
|
95% CI
|
P-value
|
|
|
Total
|
Cases
|
I2(%)
|
P-value
|
|
|
|
|
Smaller GA
|
18
|
26407
|
-
|
97.90
|
0.000
|
Random
|
1.851
|
1.112-3.081
|
0.018*
|
GA≤26w
|
5
|
14195
|
5475
|
92.90
|
0.000
|
Random
|
2.214
|
0.637-7.692
|
0.211
|
GA≤28w
|
8
|
11740
|
2150
|
78.30
|
0.000
|
Random
|
4.844
|
3.286-7.142
|
0.000**
|
GA≤32w
|
9
|
9986
|
1796
|
83.90
|
0.000
|
Random
|
3.526
|
2.382-5.219
|
0.000**
|
GA≤34w
|
4
|
7915
|
1380
|
77.30
|
0.004
|
Random
|
11.536
|
3.732-35.663
|
0.000**
|
Lower BW
|
17
|
17728
|
-
|
97.20
|
0.000
|
Random
|
1.009
|
0.995-1.022
|
0.205
|
BW≤750g
|
5
|
5302
|
1319
|
0.00
|
0.918
|
Fixed
|
2.361
|
1.683-3.313
|
0.000**
|
BW≤1,000g
|
5
|
9091
|
2796
|
92.60
|
0.000
|
Random
|
2.518
|
0.975-6.502
|
0.056
|
BW≤1,500g
|
7
|
6529
|
1048
|
74.80
|
0.001
|
Random
|
4.374
|
2.968-6.445
|
0.000**
|
BW≤2,000g
|
6
|
9824
|
1737
|
0.00
|
0.577
|
Fixed
|
6.265
|
5.331-7.362
|
0.000**
|
Male
|
15
|
21078
|
-
|
0.00
|
0.540
|
Fixed
|
1.108
|
1.03-1.191
|
0.006**
|
Multi birth
|
14
|
18909
|
-
|
75.10
|
0.000
|
Random
|
1.194
|
0.971-1.469
|
0.093
|
Oxygen therapy
|
8
|
12807
|
-
|
92.40
|
0.000
|
Random
|
1.816
|
1.063-3.104
|
0.029*
|
Cesarean section
|
9
|
15101
|
3001
|
84.40
|
0.000
|
Random
|
0.735
|
0.571-0.947
|
0.017*
|
Use of alveolar surfactant
|
7
|
6843
|
-
|
86.50
|
0.000
|
Random
|
2.234
|
1.28-3.898
|
0.005**
|
Mechanical Ventilation
|
8
|
10290
|
-
|
87.00
|
0.000
|
Random
|
2.564
|
1.547-4.248
|
0.000**
|
Invasive mechanical ventilation
|
2
|
1017
|
-
|
93.60
|
0.000
|
Random
|
3.875
|
0.923-16.266
|
0.064
|
RDS
|
8
|
7719
|
-
|
73.30
|
0.000
|
Random
|
1.881
|
1.278-2.77
|
0.001**
|
pneumonia
|
6
|
6064
|
-
|
44.00
|
0.112
|
Fixed
|
1.967
|
1.623-2.384
|
0.000**
|
PDA
|
3
|
1769
|
-
|
84.60
|
0.002
|
Random
|
2.725
|
1.341-5.534
|
0.006**
|
ART
|
5
|
8992
|
-
|
66.80
|
0.017
|
Random
|
1.328
|
0.969-1.819
|
0.077
|
IVF
|
4
|
6789
|
-
|
69.40
|
0.020
|
Random
|
1.333
|
0.84-2.116
|
0.222
|
Apnea
|
6
|
3748
|
-
|
67.50
|
0.009
|
Random
|
2.069
|
1.32-3.242
|
0.002**
|
Gestational hypertension
|
5
|
7040
|
1302
|
32.30
|
0.206
|
Fixed
|
0.926
|
0.774-1.109
|
0.403
|
Pre-eclampsia
|
3
|
1485
|
-
|
86.40
|
0.001
|
Random
|
0.920
|
0.329-2.572
|
0.873
|
Gestational diabetes
|
6
|
7923
|
-
|
36.20
|
0.166
|
Fixed
|
1.020
|
0.785-1.325
|
0.882
|
Intrauterine infection
|
2
|
2707
|
498
|
0.00
|
0.942
|
Fixed
|
1.150
|
0.902-1.466
|
0.259
|
Intrauterine distress
|
4
|
5037
|
-
|
0.00
|
0.665
|
Fixed
|
1.051
|
0.843-1.309
|
0.659
|
Respiratory distress
|
2
|
2143
|
253
|
93.10
|
0.000
|
Random
|
1.707
|
0.498-5.852
|
0.395
|
PROM
|
7
|
13084
|
-
|
22.60
|
0.257
|
Fixed
|
1.317
|
1.118-1.552
|
0.001**
|
Placental abruption
|
3
|
2252
|
355
|
0.00
|
0.537
|
Fixed
|
2.002
|
1.011-3.963
|
0.046*
|
Placenta previa
|
4
|
2418
|
449
|
0.00
|
0.614
|
Fixed
|
1.080
|
0.601-1.941
|
0.797
|
Prenatal use of steroids
|
5
|
5058
|
-
|
0.00
|
0.662
|
Fixed
|
1.388
|
1.139-1.691
|
0.001**
|
Neonatal use of steroids
|
3
|
1070
|
206
|
0.00
|
0.369
|
Fixed
|
3.254
|
1.86-5.692
|
0.000**
|
asphyxia
|
6
|
4059
|
-
|
74.20
|
0.002
|
Random
|
1.515
|
0.862-2.66
|
0.148
|
Oxygen therapy time>5d
|
2
|
850
|
-
|
0.00
|
0.718
|
Fixed
|
2.683
|
1.97-3.653
|
0.000**
|
anemia
|
7
|
4952
|
-
|
66.70
|
0.006
|
Random
|
3.286
|
2.227-4.847
|
0.000**
|
Blood transfusion
|
7
|
4796
|
-
|
86.60
|
0.000
|
Random
|
2.470
|
1.452-4.201
|
0.001**
|
Neonatal hypoglycemia
|
4
|
3184
|
-
|
0.00
|
0.622
|
Fixed
|
1.740
|
1.189-2.546
|
0.004**
|
Neonatal hyperglycemia
|
3
|
2284
|
431
|
11.40
|
0.324
|
Fixed
|
2.262
|
1.559-3.282
|
0.000**
|
Acidosis
|
2
|
1256
|
-
|
0.00
|
0.382
|
Fixed
|
1.364
|
1.042-1.788
|
0.024*
|
Cholestasis of Pregnancy
|
2
|
2118
|
337
|
0.00
|
0.869
|
Fixed
|
0.404
|
0.212-0.77
|
0.006**
|
Artificial feeding
|
2
|
3436
|
-
|
79.50
|
0.027
|
Random
|
1.227
|
0.232-6.481
|
0.809
|
septicemia
|
9
|
6027
|
-
|
42.20
|
0.086
|
Fixed
|
2.114
|
1.682-2.658
|
0.000**
|
IHE
|
4
|
2073
|
324
|
48.30
|
0.122
|
Fixed
|
1.049
|
0.665-1.655
|
0.837
|
Intracranial hemorrhage
|
6
|
3424
|
-
|
70.10
|
0.005
|
Random
|
1.473
|
0.905-2.397
|
0.119
|
BPD
|
3
|
1183
|
-
|
23.00
|
0.273
|
Fixed
|
7.281
|
5.003-10.596
|
0.000**
|
Hyperbilirubinemia
|
7
|
4872
|
-
|
59.00
|
0.023
|
Random
|
1.254
|
0.863-1.822
|
0.235
|
CHD
|
4
|
3968
|
-
|
0.00
|
0.525
|
Fixed
|
1.861
|
1.422-2.435
|
0.000**
|
Pulmonary hemorrhage
|
2
|
1780
|
300
|
0.00
|
0.981
|
Fixed
|
1.996
|
0.866-4.603
|
0.105
|
*p<0.05; **p<0.01; N, number; ES, combined effect size (OR or RR); CI, confidence interval; GA, gestational age; w, weeks; BW=birth weight; g, grams; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; ART, artificial reproductive technology; IVF, in vitro fertilization; PROM, premature rupture of membranes; d, days; HIE, hypoxic-ischemic encephalopathy; BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; Random, random effects model; Fixed, fixed effects model.
The results showed that smaller GA, GA≤28 w, GA≤32 w, GA≤34 w, BW≤750 g, BW≤1,500 g, BW≤2,000 g, the male sex, oxygen therapy, cesarean sections, uses of alveolar surfactant, mechanical ventilation, RDS, pneumonia, PDA, apnea, PROM, placental abruption, the prenatal use of steroids, the neonatal use of steroids, oxygen therapy time>5d, anemia, blood transfusion, neonatal hypoglycemia, neonatal hyperglycemia, acidosis, cholestasis of pregnancy, septicemia, BPD and congenital heart disease (a total of 30 variables) were significantly related to the occurrence of ROP (p<0.05). Among them, the two variables of cesarean section (OR: 0.735, 95% CI: 0.571-0.947) and cholestasis of pregnancy (OR: 0.404, 95% CI: 0.212-0.770) had protective effects on the occurrence of ROP. The other 28 variables were risk factors for the occurrence of ROP (OR>1).
Other risk factors for ROP
In addition, risk factors that were not included in the meta-analysis were mentioned in some articles (Table 3).
Table 3. Other risk factors of ROP in China
|
Variable
|
Sample (N)
|
ES
|
95%CI
|
Type of ES
|
P-value
|
Maternal supplemental oxygen administration
|
468
|
6.090
|
2.200 - 16.880
|
OR
|
0.000**
|
Intravascular hemolysis
|
436
|
3.095
|
2.037 - 4.701
|
OR
|
0.000**
|
Acid-base imbalance
|
1614
|
2.197
|
1.491 - 3.192
|
OR
|
0.000**
|
Maternal cold
|
1614
|
1.630
|
0.983 - 2.615
|
OR
|
0.036*
|
Hypoproteinemia
|
1614
|
3.122
|
2.023 - 4.742
|
OR
|
0.000**
|
Erythropoietin
|
1614
|
2.178
|
1.112 - 4.041
|
OR
|
0.009**
|
Encephalopathy of preterm infants
|
1614
|
2.755
|
1.986 - 3.804
|
OR
|
0.000**
|
Myocardial injury
|
1614
|
1.655
|
1.158 - 2.341
|
OR
|
0.003**
|
Coagulation dysfunction
|
1614
|
1.919
|
1.299 - 2.795
|
OR
|
0.000**
|
Vasoactive substances
|
1614
|
3.161
|
2.187 - 4.529
|
OR
|
0.000**
|
Vitamin A supplement
|
262
|
0.601
|
0.465 - 0.775
|
RR
|
0.000**
|
Apgar score 1 min<4
|
4977
|
2.152
|
1.758 - 2.633
|
RR
|
0.000**
|
Postnatal hypotension
|
513
|
6.760
|
4.120 - 11.160
|
OR
|
<0.001**
|
Inotrope use
|
513
|
7.700
|
4.460 - 13.390
|
OR
|
<0.001**
|
NSAID use
|
513
|
6.530
|
3.940 - 10.860
|
OR
|
<0.001**
|
Thrombocytopenia
|
513
|
2.870
|
1.630 - 4.990
|
OR
|
<0.001**
|
Phototherapy
|
513
|
2.980
|
1.360 - 7.890
|
OR
|
<0.001**
|
*p<0.05; **p<0.01; N, number; ES, combined effect size (OR or RR); CI, confidence interval.
In addition to risk factors such as BW and GA, a study by Liu Q et al.29 (with a sample size of 1,614 cases) also showed that acid-base imbalance, maternal cold, hypoproteinemia, erythropoietin, encephalopathy of preterm infants, myocardial injury, coagulation dysfunction and vasoactive substances were also risk factors for ROP (OR>1, p<0.05). Yau GS et al.30 showed that hypotension, cardiotonic use, NSAID use, thrombocytopenia and light therapy were also risk factors for ROP (OR>1, p<0.05) in another study. A 5-year cohort study by Yang Q et al.31 suggested that 1 min Apgar<4 points was a risk factor for ROP (RR>1, p<0.05). Furthermore, oxygen therapy during pregnancy and intravascular hemolysis were mentioned as being risk factors for ROP32,33. Vitamin A supplementation in infants was found to reduce the incidence of ROP in very premature infants (RR=0.601, 95% CI: 0.465-0.775, p=0.000)34.