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Characterization of the Progression Pattern in Retinopathy of Prematurity Subtypes
Journal Pre-proof Characterization of the progression pattern in retinopathy of prematurity subtypes Yoko Fukushima, MD, PhD, Ryo Kawasaki, MD, PhD, Hirokazu Sakaguchi, MD, PhD, Andrew Winegarner, MS, Hiromi Ineyama, BA, Yousuke Imanishi, MD, Shinya Hirano, MD, Kazuko Wada, MD, Yoshikazu Hatsukawa, MD, PhD, Kohji Nishida, MD, PhD PII:
S2468-6530(19)30649-9
DOI:
https://doi.org/10.1016/j.oret.2019.11.015
Reference:
ORET 666
To appear in:
Ophthalmology Retina
Received Date: 15 August 2019 Revised Date:
11 November 2019
Accepted Date: 15 November 2019
Please cite this article as: Fukushima Y., Kawasaki R., Sakaguchi H., Winegarner A., Ineyama H., Imanishi Y., Hirano S., Wada K., Hatsukawa Y. & Nishida K., Characterization of the progression pattern in retinopathy of prematurity subtypes, Ophthalmology Retina (2019), doi: https://doi.org/10.1016/ j.oret.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © YEAR Published by Elsevier Inc. on behalf of American Academy of Ophthalmology
1
Characterization of the progression pattern in retinopathy of prematurity subtypes
Yoko Fukushima, MD, PhD1, Ryo Kawasaki, MD, PhD1, Hirokazu Sakaguchi, MD, PhD1, Andrew Winegarner, MS1, 2, Hiromi Ineyama, BA3, Yousuke Imanishi, MD4, Shinya Hirano, MD4, Kazuko Wada, MD4, Yoshikazu Hatsukawa, MD, PhD3, Kohji Nishida, MD, PhD1
1
Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan;
2
Department of Ophthalmology, Kansas University Medical Center, School of Medicine,
Kansas City, KS, USA; 3Department of Ophthalmology, Osaka Women’s and Children’s Hospital, Osaka, Japan; 4Department of Neonatal Medicine, Osaka Women’s and Children’s Hospital, Osaka, Japan.
Corresponding author: Yoko Fukushima, MD, PhD, Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, E-7, Suita, Osaka 565-0871, Japan Phone: +81-6-6879-3456, fax: +81-6-6879-3458 E-mail: [email protected]
Manuscript Category: Full Length Article
Word count: 2284
Running head: Progression pattern in retinopathy of prematurity subtypes
Address for reprints: Yoko Fukushima, Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2
Abbreviations and Acronyms: AP-ROP, aggressive posterior retinopathy of prematurity; BW, birth weight; ETROP, Early Treatment for Retinopathy of Prematurity; GA, gestational age; NICU, neonatal intensive care unit; PMA, postmenstrual age; ROP, retinopathy of prematurity; VEGF, vascular endothelial growth factor
Conflict of Interest: No conflicting relationship exists for any author.
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.
This work is supported by the Japan Society for the Promotion of Science KAKENHI grant 17K17859 with additional funding from the Takeda Science Foundation.
Author Contributions: Conception and design: YF Analysis and interpretation: YF, RK, HS, AW, YI, SH, KW, YH, KN Data acquisition and research execution: YF, RK, HI, YI, SH, KW Manuscript preparation: YF Critical Review of Manuscript: YF, RK, HS, AW, HI, YI, SH, KW, YH, KN
3
Abstract Purpose: To evaluate differences in the progression pattern between subtypes of retinopathy of prematurity (ROP). Design: Retrospective cohort study Subjects: Premature infants screened for ROP Methods: Medical records of 578 premature infants who were screened at the neonatal intensive care unit from September 2009 to March 2016 were reviewed. We matched for the number of patients, gestational age at birth, and postmenstrual age at the first examination between infants with spontaneously regressed ROP and those with treated ROP A total of 133 premature infants who were born before 27 weeks’ gestation were finally included. Main Outcome Measures: The mean age at onset of any ROP and the duration from the initial examination to onset were compared between infants with regressed ROP and those with treated ROP. The mean age at treatment and the duration from onset to treatment were compared between infants with type 1 ROP and those with aggressive posterior ROP (AP-ROP). Data were analyzed for one randomly selected eye for each infant. Results: Of 133 premature infants with any ROP, 67 regressed spontaneously, 43 developed type 1 ROP, and 23 developed AP-ROP. Individual trajectories of ROP progression over time showed that AP-ROP progressed through the stages in a steep linear manner in most cases. In contrast, the type 1 ROP and regressed ROP groups developed in a slower, stepwise manner. Conclusions: In infants with ROP, the disease trajectories across ROP stages are different based on the ROP subtype, despite postmenstrual age at onset being comparable across subtypes. Our findings could be useful for managing follow-up screening.
4
1
Retinopathy of prematurity (ROP) is a major cause of blindness in children worldwide1, 2. Over
2
the last decade, there have been several advances in the management of ROP. First, revised
3
treatment indications from the Early Treatment for ROP (ETROP) study have contributed to
4
better outcomes.3 Second, anti-vascular endothelial growth factor (VEGF) drugs have emerged
5
as a new treatment option.4, 5 To maximize the benefit of advances in treatment, the timing of
6
treatment for ROP is critical.
7
The narrow therapeutic time window for preventing retinal detachment is challenging
8
in the treatment for ROP. Additionally, subtypes with different progression make it difficult to
9
determine when to treat. Among subtypes of ROP, aggressive posterior ROP (AP-ROP) is
10
known to be a rapid progressing subtype, with a poor prognosis in premature infants.6, 7 Howev-
11
er, early detection of AP-ROP remains difficult even for ROP experts because AP-ROP neither
12
has clear-cut quantitative criteria for diagnosis nor follows the classic stages of typical ROP.6, 8
13
Previous studies have reported the natural history of ROP such as the time course of
14
disease progression by subtypes.9-12 However, there is a little known regarding whether the pro-
15
gression of ROP has individual differences among infants within the same subtype. Therefore,
16
we specifically assessed the progression trajectory of each individual patient so as to determine
17
if the trajectories themselves showed patterns unique to each subtype. Our findings could be
18
useful for better understanding of ROP subtypes and performing follow-up examinations in
19
management of ROP.
20 21
Patients and Methods
22
We designed this study to determine differences in progression patterns among ROP subtypes,
23
including spontaneously regressed ROP, type 1 ROP, and AP-ROP. This was a retrospective
24
cohort study of all consecutive preterm infants who underwent eye examinations at the neonatal
25
intensive care unit (NICU) of a single institution in Japan from September 2009 to March 2016.
26
The study was conducted with the approval of the Ethical Review Board of Osaka Women’s and
27
Children’s Hospital, and adhered to the tenets of the Declaration of Helsinki (1964). An opt-out
5
28
consent method was used to participate in this study. This study enrolled premature infants with
29
< 27 weeks’ gestational age (GA) and with any ROP. Exclusion criteria were the followings:
30
infants with chromosomal disorders, multiple anomalies, metabolic disease, systemic bone dis-
31
ease, vertical infection, and others, and infants who were transferred to other hospitals before
32
the ROP outcome was determined. The screening timing followed the guideline provided by the
33
American Academy of Ophthalmology with some modifications. The initial fundus examination
34
was performed at 29 or 30 weeks of postmenstrual age (PMA) unless there were special cir-
35
cumstances. Follow-up examinations were scheduled more than once a week if vascular exten-
36
sion was present within zone I or posterior zone II.13 ROP was diagnosed according to the In-
37
ternational Classification of ROP revisited.6 The requirements for diagnosing AP-ROP at the
38
time of examination were defined as plus disease in all quadrants and flat neovascularization
39
located at zone
40
ETROP Cooperative Group3 by two ophthalmologists (Y.F and Y.H) with expertise in ROP. Un-
41
less there were particular reasons, type 1 ROP and AP-ROP were treated on the same day of
42
diagnosis. Demographic and ophthalmological data, including sex, birth weight (BW), GA, type
43
of ROP, and ROP stages at every examination, were collected from the medical records. The
44
endpoint of data collection was defined as the time when ROP regressed with full vasculariza-
45
tion or progressed enough to require any treatment.
46
Outcomes and statistical analysis
47
The median age at onset of any ROP and the duration from the initial examination to onset were
48
compared among infants with regressed ROP, type 1 ROP and AP-ROP. The median age at
49
treatment and the duration from onset to treatment were compared between infants with type 1
50
ROP and those with AP-ROP. Individual trajectories of each patient as they progressed across
51
ROP stages and plus disease were longitudinally plotted, and then grouped together according to
52
their subtype. The incidence of infants who reached stage 3 and plus disease was determined by
53
Kaplan–Meier survival analysis and compared among subtypes. Variables were compared using
54
one-way analysis of variance, the Mann–Whitney U test, or Pearson’s chi-square test. A P value
or posterior zone
. ROP was treated according to the recommendation of the
6
55
< 0.05 was considered statistically significant. One randomly selected eye from each infant was
56
used for analysis.
57 58
Results
59
A flowchart of the patients’ enrollment is shown in Figure 1. A total of 578 infants were
60
screened at the NICU, and finally, 133 infants with any ROP and with < 27 weeks’ GA were
61
enrolled. The characteristics and clinical courses of 133 infants are shown in Table 1. Among
62
them, 67 infants regressed ROP spontaneously, 43 developed type 1 ROP, and 23 developed
63
AP-ROP. There were significant differences in BW and GA among the three groups. The medi-
64
an BW was 654g for regressed ROP, 666g for type 1ROP, and 564g for APROP (P = 0.007).
65
The median GA was 25.0 weeks for regressed ROP, 25.0 weeks for type 1 ROP, and 23.7 weeks
66
for AP-ROP (P < 0.001).
67
In comparison with the time course of ROP progression, the median PMA of onset did
68
not differ among the three groups (P = 0.08). However, the median PMA at initial treatment for
69
type 1 ROP was significantly later than that of AP-ROP (P <0.001). At the initial examination,
70
blot hemorrhage on the vascularized retina was observed in 17% (4/23) of infants in the
71
AP-ROP group, 9% (4/44) in the type 1 ROP group, and 4% (3/67) in the regressed ROP group,
72
with no significant difference among the groups (P = 0.14). Of 23 infants with AP-ROP, three
73
(13% of the patients with AP-ROP, 4.5% of all treated patients) required treatment on the day of
74
the initial examination. None of the infants had developed type 1 ROP on the initial examination
75
day. Six infants developed ROP that required treatment on the same day as being newly diag-
76
nosed with any ROP at the second or later examinations. Five of these six infants had AP-ROP.
77
The numbers of screened infants by PMA are shown in Table 2. Based on the data from
78
sequential follow-up screening, details of individual trajectories of progression are plotted in
79
Figure 2. AP-ROP progressed through the stages in an approximately linear, fairly steep manner
80
in most cases. In contrast, the type 1 ROP and regressed ROP groups developed in a slower
81
stepwise manner; therefore, these ROP subtypes remained at the same stage for a while and then
7
82
become worse in small increments. The median PMA when infants were initially diagnosed
83
with plus disease was later in type 1 ROP than in AP-ROP. Among 67 infants in the regressed
84
group, 12 (17.9%) progressed to stage 3. In the treated groups of type 1 ROP and AP-ROP, there
85
were no infants with newly developed stage 3 and plus disease after 39.1 weeks and 36 weeks
86
of PMA, respectively. The cumulative probability of infants who were diagnosed with stage 3 or
87
plus disease showed that 95% of infants with stage 3 or plus disease by 36 weeks’ PMA re-
88
quired treatment, whereas 60% of infants with stage 3 after 36 weeks’ PMA spontaneously re-
89
gressed (Figure 3).
90 91
Discussion
92
To date, a number of studies have reported the typical course of ROP will often follow.9-12
93
However, most of them have focused little on the individual patterns of ROP progression. We
94
previously reported the individual trajectories of progression in premature infants with zone 1
95
ROP between 2000 and 2006.14 In the current cohort, we clearly visualized the progression pat-
96
terns by ROP subtypes. AP-ROP often developed within 1 week from onset, and type 1 ROP
97
developed 3 weeks from onset. The individual trajectories showed AP-ROP had a worsening
98
condition at every examination, as shown by steep linear progression with minimal individual
99
variation between patients. Type 1 ROP worsened more slowly as it advanced through the stages,
100
which was observed as stepwise progression. The progression pattern of regressed ROP was
101
similar to that of type 1 ROP, but was seen to be an even slower could be represented as more
102
slowly stepwise progression.
103
Although we did not find a difference in PMA at onset among subtypes, the distinct
104
progression patterns in the subtypes were obvious, which may contribute to better understanding
105
for subtypes. Since AP-ROP was defined in 2005,6 this severe subtype has not been described in
106
detail regarding how rapidly it progresses. One difficulty in early diagnosis of AP-ROP is due to
107
unclear minimal changes in retinal vessels at early phase. Additionally, in clinical setting, in-
108
fants who would have gone on to develop to AP-ROP may receive treatment before it might
8
109
reach prominent plus disease. Since AP-ROP is not easily distinguished from zone
110
ROP in some cases, it is highly likely that the case would have been diagnosed with AP-ROP
111
when the disease recurrence occurred after initial treatment.7, 15 Recently, ROP experts have
112
suspected that AP-ROP is not a separate subtype, but rather on a spectrum of type 1 ROP.16 In
113
this retrospective study, individual trajectories of the disease course showed that progression of
114
AP-ROP was clinically more homogeneous than type 1 ROP and regressed ROP. Therefore,
115
AP-ROP might have specific pathophysiological features. Given that extraretinal blood vessels
116
regress spontaneously in most ROP,6 developmental retinal angiogenesis can be said to have
117
robustness in directional vascular expansion. There is no doubt that higher VEGF stimulates
118
growth of aberrant blood vessels in retina.2, 17 However, complete understanding on whether
119
increasing VEGF levels lose this robustness or not and determining the progression patterns of
120
ROP, both require further investigation.
121
stage 3+
Ultimately, it would be beneficial for ROP management to identify specific findings
122
to distinguish AP-ROP from type 1 ROP and regressed ROP in advance. In our study, we ob-
123
served blot hemorrhage on vascularized retina at the initial examination as a conspicuous retinal
124
finding. There was an increasing trend of this finding consistent with the severity of ROP sub-
125
types. However, blot hemorrhage at the initial examination was not significantly different
126
among the groups. The e-ROP study group reported that blot hemorrhage was a predictive factor
127
of ROP that required treatment.18 While blot hemorrhage at an initial exam might be a potential
128
risk factor of developing severe ROP, identification of specific findings for subtypes is still
129
challenging. Image analysis, systemic comorbidity assessment, and other technical develop-
130
ments are necessary to provide new predictive factors for ROP subtype.
131
Limitations in this study include its retrospective nature, small sample size, and all
132
cases being from a single institute. The rates of infants with any ROP and those with ROP that
133
required treatment in this study are higher than those in previous studies in the USA. To date,
134
Alaskan natives and Asians have a higher risk of developing severe ROP than do
135
Caucasians.19-21 Because ethnicity/race affects the severity of ROP, the Japanese pediatric popu-
9
136
lation might have a higher risk for developing ROP than Caucasians. With regard to disease
137
onset and the natural course of ROP, we previously reported that the median PMA at onset and
138
at treatment was 32 and 34 weeks, respectively, in infants with zone 1 ROP who were born with
139
a BW < 1250 g between 2000 and 2006.14 In the current cohort, the median PMA at onset of
140
ROP and at treatment was 31 and 34 weeks, respectively. In extremely premature infants at a
141
high risk of ROP, disease onset and the natural course have not changed for almost 2 decades in
142
our institute. Other studies from the USA and Sweden reported that the median PMA at onset
143
and stage 3 ROP were approximately 34 and 36 weeks, respectively.10, 11 Quinn et al showed
144
that onset and progression of ROP have remained stable for the last 3 decades in the USA,11
145
which is consistent with our results. However, the reason for the earlier onset and treatment in
146
our cohort still remains to be clarified. The earlier peak shift may be explained by genetic back-
147
ground and race. Moreover, the reason for onset being comparable across subtypes may be at-
148
tributed to the pathophysiology of ROP. When this disease develops, a delay in vascular growth
149
and capillary dropout at the angiogenic front are switched to outgrowth of abnormal extraretinal
150
blood vessels.17 Most infants with a GA < 27 weeks receive respiratory support and oxygen use
151
from birth.22 Therefore, an oxygen-induced delay in vascular growth and capillary dropout often
152
occur in the developing retina of these premature infants. Constriction of capillaries induces
153
excess VEGF expression, resulting in formation of extraretinal blood vessels. Increasing VEGF
154
levels can cause onset of ROP at a specific period, regardless of ROP subtypes. These possible
155
explanations for the timing of onset in our study need to be verified in future research. Addi-
156
tionally, whether the trend found in this study could be applied for other socioeconomic circum-
157
stances, other races/ethnicities, and other NICU settings is unknown.
158
A notable feature of our study is that we evaluated individual trajectories of each pa-
159
tient’s disease course among subtypes for defining characteristics of the progression pattern. In
160
management of ROP, timely and appropriate treatment is necessary to prevent visual loss.2
161
Therefore, ophthalmologists should carefully observe not to miss the therapeutic window. Our
162
findings of the ROP progression pattern by subtype in extremely premature infants could help to
10
163
perform follow-up examinations. When the onset of ROP is initially diagnosed, if the subtype
164
ends up being AP-ROP, the ROP will continues to deteriorate through the stage as seen on serial
165
examination and will likely require treatment within 1 week. If ROP develops to stage 3 after 36
166
weeks of PMA, more than half of infants achieve regression of ROP without treatment. Taken
167
together, these trends should be helpful in monitoring early disease progression and possibly
168
point towards a common pathophysiology behind the AP-ROP given the homogenous nature of
169
the individual trajectories observed in that subtype.
170 171 172 173 174
11
175
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14
232
Figure Legends
233
Figure 1. Flowchart of enrollment of the study population.
234
NICU, neonatal intensive care unit; ROP, retinopathy of prematurity; AP-ROP, aggressive pos-
235
terior retinopathy of prematurity; GA, gestational age.
236 237
Figure 2. Individual progression trajectories of infants with a GA < 27 weeks. Graphs show the
238
time to progression of ROP stages (left) and plus disease (right) in infants with AP-ROP, type 1
239
ROP, and regressed ROP. The values of plus in the vertical axis of the right panel indicate the
240
following: 1, pre-plus disease; and 2, plus disease. The endpoint of each trajectory indicates the
241
time when ROP regressed with full vascularization or progressed to the point of requiring any
242
treatment.
243
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity;
244
PMA, postmenstrual age.
245 246
Figure 3. Cumulative probability of infants who were diagnosed with stage 3 and/or plus dis-
247
ease. Kaplan–Meier failure curves show the time to progression in infants with AP-ROP, type 1
248
ROP, and regressed ROP. The horizontal and vertical dotted lines define 15% of cumulative
249
probability and 36 weeks' PMA, respectively. The PMAs when 15% of infants with AP-ROP,
250
type 1 ROP, and regressed ROP progressed to stage 3 and/or plus disease were 30.1 weeks, 32.4
251
weeks, and 38.4 weeks, respectively. Note that 95% of infants with stage 3 or plus disease by 36
252
weeks’ PMA required treatment, whereas 60% of infants with stage 3 after 36 weeks’ PMA re-
253
gressed spontaneously.
254
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity;
255
PMA, postmenstrual age.
256
1
1
Table 1. Characteristics and clinical courses of 133 premature infants
No. of patients Male gender, no. (%)
Regressed
Type 1 ROP
AP-ROP
67
43
23
33 (49.2)
16 (37.2)
10 (43.4)
BW (g)
.46 .0072
Median
654
666
564
Range
458 – 1102
394 – 1024
450 – 802
GA (weeks)
< .001
Median
25.0
25.0
23.7
Range
22.2 – 26.8
22.2 -26.7
22.5 – 25.4
PMA at initial exam (weeks)
.49
Median
29.5
29.5
29.7
Range
28.1 – 31.1
28.2 – 32.2
29.0 – 30.7
PMA at onset (weeks)
.08
Median
31.4
31.5
31.1
Range
29.2 – 42.1
29.2 -34.1
29.7 – 32.8
Duration between initial exam and onset (days)
.08
Median
14
14
9
Range
0 - 91
0 - 28
0 -14
PMA at initial treatment (weeks)
P value
< .001
2
Median
34.5
32.1
Range
31.1 – 42.2
30.0 – 35.4
Duration between onset and initial treatment (days)
< .001
Median
21
5
Range
0 - 73
0 - 17
2
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity; BW, birth weight; GA, gestational age; PMA,
3
postmenstrual age.
4 5 6 7 8 9 10
1
1
Table 2. Total number of infants screened according to PMA Regressed ROP (N = 67)
2
Type 1 ROP (N =43)
AP-ROP (N = 23)
PMA (weeks)
No. of screened patients (No. of treated patients)
< 29
4
1 (0)
0 (0)
29
49
36 (0)
15 (0)
30
60
40 (0)
23 (5)
31
66
41 (1)
18 (4)
32
66
41 (4)
14 (12)
33
63
36 (12)
2 (1)
34
60
26 (6)
1 (0)
35
55
20 (7)
1 (1)
36
53
13 (4)
0
37
44
9 (4)
0
38
49
5 (1)
0
39
43
4 (1)
0
40 ≦
64
3 (3)
0
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity; PMA, postmenstrual age.
Précis We assessed individual trajectories across stages of retinopathy of prematurity (ROP). Aggressive posterior ROP progressed through the stages in a linear manner. In contrast, type 1 ROP and regressed ROP developed in a stepwise manner.
S2468-6530(19)30649-9
DOI:
https://doi.org/10.1016/j.oret.2019.11.015
Reference:
ORET 666
To appear in:
Ophthalmology Retina
Received Date: 15 August 2019 Revised Date:
11 November 2019
Accepted Date: 15 November 2019
Please cite this article as: Fukushima Y., Kawasaki R., Sakaguchi H., Winegarner A., Ineyama H., Imanishi Y., Hirano S., Wada K., Hatsukawa Y. & Nishida K., Characterization of the progression pattern in retinopathy of prematurity subtypes, Ophthalmology Retina (2019), doi: https://doi.org/10.1016/ j.oret.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © YEAR Published by Elsevier Inc. on behalf of American Academy of Ophthalmology
1
Characterization of the progression pattern in retinopathy of prematurity subtypes
Yoko Fukushima, MD, PhD1, Ryo Kawasaki, MD, PhD1, Hirokazu Sakaguchi, MD, PhD1, Andrew Winegarner, MS1, 2, Hiromi Ineyama, BA3, Yousuke Imanishi, MD4, Shinya Hirano, MD4, Kazuko Wada, MD4, Yoshikazu Hatsukawa, MD, PhD3, Kohji Nishida, MD, PhD1
1
Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan;
2
Department of Ophthalmology, Kansas University Medical Center, School of Medicine,
Kansas City, KS, USA; 3Department of Ophthalmology, Osaka Women’s and Children’s Hospital, Osaka, Japan; 4Department of Neonatal Medicine, Osaka Women’s and Children’s Hospital, Osaka, Japan.
Corresponding author: Yoko Fukushima, MD, PhD, Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, E-7, Suita, Osaka 565-0871, Japan Phone: +81-6-6879-3456, fax: +81-6-6879-3458 E-mail: [email protected]
Manuscript Category: Full Length Article
Word count: 2284
Running head: Progression pattern in retinopathy of prematurity subtypes
Address for reprints: Yoko Fukushima, Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2
Abbreviations and Acronyms: AP-ROP, aggressive posterior retinopathy of prematurity; BW, birth weight; ETROP, Early Treatment for Retinopathy of Prematurity; GA, gestational age; NICU, neonatal intensive care unit; PMA, postmenstrual age; ROP, retinopathy of prematurity; VEGF, vascular endothelial growth factor
Conflict of Interest: No conflicting relationship exists for any author.
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.
This work is supported by the Japan Society for the Promotion of Science KAKENHI grant 17K17859 with additional funding from the Takeda Science Foundation.
Author Contributions: Conception and design: YF Analysis and interpretation: YF, RK, HS, AW, YI, SH, KW, YH, KN Data acquisition and research execution: YF, RK, HI, YI, SH, KW Manuscript preparation: YF Critical Review of Manuscript: YF, RK, HS, AW, HI, YI, SH, KW, YH, KN
3
Abstract Purpose: To evaluate differences in the progression pattern between subtypes of retinopathy of prematurity (ROP). Design: Retrospective cohort study Subjects: Premature infants screened for ROP Methods: Medical records of 578 premature infants who were screened at the neonatal intensive care unit from September 2009 to March 2016 were reviewed. We matched for the number of patients, gestational age at birth, and postmenstrual age at the first examination between infants with spontaneously regressed ROP and those with treated ROP A total of 133 premature infants who were born before 27 weeks’ gestation were finally included. Main Outcome Measures: The mean age at onset of any ROP and the duration from the initial examination to onset were compared between infants with regressed ROP and those with treated ROP. The mean age at treatment and the duration from onset to treatment were compared between infants with type 1 ROP and those with aggressive posterior ROP (AP-ROP). Data were analyzed for one randomly selected eye for each infant. Results: Of 133 premature infants with any ROP, 67 regressed spontaneously, 43 developed type 1 ROP, and 23 developed AP-ROP. Individual trajectories of ROP progression over time showed that AP-ROP progressed through the stages in a steep linear manner in most cases. In contrast, the type 1 ROP and regressed ROP groups developed in a slower, stepwise manner. Conclusions: In infants with ROP, the disease trajectories across ROP stages are different based on the ROP subtype, despite postmenstrual age at onset being comparable across subtypes. Our findings could be useful for managing follow-up screening.
4
1
Retinopathy of prematurity (ROP) is a major cause of blindness in children worldwide1, 2. Over
2
the last decade, there have been several advances in the management of ROP. First, revised
3
treatment indications from the Early Treatment for ROP (ETROP) study have contributed to
4
better outcomes.3 Second, anti-vascular endothelial growth factor (VEGF) drugs have emerged
5
as a new treatment option.4, 5 To maximize the benefit of advances in treatment, the timing of
6
treatment for ROP is critical.
7
The narrow therapeutic time window for preventing retinal detachment is challenging
8
in the treatment for ROP. Additionally, subtypes with different progression make it difficult to
9
determine when to treat. Among subtypes of ROP, aggressive posterior ROP (AP-ROP) is
10
known to be a rapid progressing subtype, with a poor prognosis in premature infants.6, 7 Howev-
11
er, early detection of AP-ROP remains difficult even for ROP experts because AP-ROP neither
12
has clear-cut quantitative criteria for diagnosis nor follows the classic stages of typical ROP.6, 8
13
Previous studies have reported the natural history of ROP such as the time course of
14
disease progression by subtypes.9-12 However, there is a little known regarding whether the pro-
15
gression of ROP has individual differences among infants within the same subtype. Therefore,
16
we specifically assessed the progression trajectory of each individual patient so as to determine
17
if the trajectories themselves showed patterns unique to each subtype. Our findings could be
18
useful for better understanding of ROP subtypes and performing follow-up examinations in
19
management of ROP.
20 21
Patients and Methods
22
We designed this study to determine differences in progression patterns among ROP subtypes,
23
including spontaneously regressed ROP, type 1 ROP, and AP-ROP. This was a retrospective
24
cohort study of all consecutive preterm infants who underwent eye examinations at the neonatal
25
intensive care unit (NICU) of a single institution in Japan from September 2009 to March 2016.
26
The study was conducted with the approval of the Ethical Review Board of Osaka Women’s and
27
Children’s Hospital, and adhered to the tenets of the Declaration of Helsinki (1964). An opt-out
5
28
consent method was used to participate in this study. This study enrolled premature infants with
29
< 27 weeks’ gestational age (GA) and with any ROP. Exclusion criteria were the followings:
30
infants with chromosomal disorders, multiple anomalies, metabolic disease, systemic bone dis-
31
ease, vertical infection, and others, and infants who were transferred to other hospitals before
32
the ROP outcome was determined. The screening timing followed the guideline provided by the
33
American Academy of Ophthalmology with some modifications. The initial fundus examination
34
was performed at 29 or 30 weeks of postmenstrual age (PMA) unless there were special cir-
35
cumstances. Follow-up examinations were scheduled more than once a week if vascular exten-
36
sion was present within zone I or posterior zone II.13 ROP was diagnosed according to the In-
37
ternational Classification of ROP revisited.6 The requirements for diagnosing AP-ROP at the
38
time of examination were defined as plus disease in all quadrants and flat neovascularization
39
located at zone
40
ETROP Cooperative Group3 by two ophthalmologists (Y.F and Y.H) with expertise in ROP. Un-
41
less there were particular reasons, type 1 ROP and AP-ROP were treated on the same day of
42
diagnosis. Demographic and ophthalmological data, including sex, birth weight (BW), GA, type
43
of ROP, and ROP stages at every examination, were collected from the medical records. The
44
endpoint of data collection was defined as the time when ROP regressed with full vasculariza-
45
tion or progressed enough to require any treatment.
46
Outcomes and statistical analysis
47
The median age at onset of any ROP and the duration from the initial examination to onset were
48
compared among infants with regressed ROP, type 1 ROP and AP-ROP. The median age at
49
treatment and the duration from onset to treatment were compared between infants with type 1
50
ROP and those with AP-ROP. Individual trajectories of each patient as they progressed across
51
ROP stages and plus disease were longitudinally plotted, and then grouped together according to
52
their subtype. The incidence of infants who reached stage 3 and plus disease was determined by
53
Kaplan–Meier survival analysis and compared among subtypes. Variables were compared using
54
one-way analysis of variance, the Mann–Whitney U test, or Pearson’s chi-square test. A P value
or posterior zone
. ROP was treated according to the recommendation of the
6
55
< 0.05 was considered statistically significant. One randomly selected eye from each infant was
56
used for analysis.
57 58
Results
59
A flowchart of the patients’ enrollment is shown in Figure 1. A total of 578 infants were
60
screened at the NICU, and finally, 133 infants with any ROP and with < 27 weeks’ GA were
61
enrolled. The characteristics and clinical courses of 133 infants are shown in Table 1. Among
62
them, 67 infants regressed ROP spontaneously, 43 developed type 1 ROP, and 23 developed
63
AP-ROP. There were significant differences in BW and GA among the three groups. The medi-
64
an BW was 654g for regressed ROP, 666g for type 1ROP, and 564g for APROP (P = 0.007).
65
The median GA was 25.0 weeks for regressed ROP, 25.0 weeks for type 1 ROP, and 23.7 weeks
66
for AP-ROP (P < 0.001).
67
In comparison with the time course of ROP progression, the median PMA of onset did
68
not differ among the three groups (P = 0.08). However, the median PMA at initial treatment for
69
type 1 ROP was significantly later than that of AP-ROP (P <0.001). At the initial examination,
70
blot hemorrhage on the vascularized retina was observed in 17% (4/23) of infants in the
71
AP-ROP group, 9% (4/44) in the type 1 ROP group, and 4% (3/67) in the regressed ROP group,
72
with no significant difference among the groups (P = 0.14). Of 23 infants with AP-ROP, three
73
(13% of the patients with AP-ROP, 4.5% of all treated patients) required treatment on the day of
74
the initial examination. None of the infants had developed type 1 ROP on the initial examination
75
day. Six infants developed ROP that required treatment on the same day as being newly diag-
76
nosed with any ROP at the second or later examinations. Five of these six infants had AP-ROP.
77
The numbers of screened infants by PMA are shown in Table 2. Based on the data from
78
sequential follow-up screening, details of individual trajectories of progression are plotted in
79
Figure 2. AP-ROP progressed through the stages in an approximately linear, fairly steep manner
80
in most cases. In contrast, the type 1 ROP and regressed ROP groups developed in a slower
81
stepwise manner; therefore, these ROP subtypes remained at the same stage for a while and then
7
82
become worse in small increments. The median PMA when infants were initially diagnosed
83
with plus disease was later in type 1 ROP than in AP-ROP. Among 67 infants in the regressed
84
group, 12 (17.9%) progressed to stage 3. In the treated groups of type 1 ROP and AP-ROP, there
85
were no infants with newly developed stage 3 and plus disease after 39.1 weeks and 36 weeks
86
of PMA, respectively. The cumulative probability of infants who were diagnosed with stage 3 or
87
plus disease showed that 95% of infants with stage 3 or plus disease by 36 weeks’ PMA re-
88
quired treatment, whereas 60% of infants with stage 3 after 36 weeks’ PMA spontaneously re-
89
gressed (Figure 3).
90 91
Discussion
92
To date, a number of studies have reported the typical course of ROP will often follow.9-12
93
However, most of them have focused little on the individual patterns of ROP progression. We
94
previously reported the individual trajectories of progression in premature infants with zone 1
95
ROP between 2000 and 2006.14 In the current cohort, we clearly visualized the progression pat-
96
terns by ROP subtypes. AP-ROP often developed within 1 week from onset, and type 1 ROP
97
developed 3 weeks from onset. The individual trajectories showed AP-ROP had a worsening
98
condition at every examination, as shown by steep linear progression with minimal individual
99
variation between patients. Type 1 ROP worsened more slowly as it advanced through the stages,
100
which was observed as stepwise progression. The progression pattern of regressed ROP was
101
similar to that of type 1 ROP, but was seen to be an even slower could be represented as more
102
slowly stepwise progression.
103
Although we did not find a difference in PMA at onset among subtypes, the distinct
104
progression patterns in the subtypes were obvious, which may contribute to better understanding
105
for subtypes. Since AP-ROP was defined in 2005,6 this severe subtype has not been described in
106
detail regarding how rapidly it progresses. One difficulty in early diagnosis of AP-ROP is due to
107
unclear minimal changes in retinal vessels at early phase. Additionally, in clinical setting, in-
108
fants who would have gone on to develop to AP-ROP may receive treatment before it might
8
109
reach prominent plus disease. Since AP-ROP is not easily distinguished from zone
110
ROP in some cases, it is highly likely that the case would have been diagnosed with AP-ROP
111
when the disease recurrence occurred after initial treatment.7, 15 Recently, ROP experts have
112
suspected that AP-ROP is not a separate subtype, but rather on a spectrum of type 1 ROP.16 In
113
this retrospective study, individual trajectories of the disease course showed that progression of
114
AP-ROP was clinically more homogeneous than type 1 ROP and regressed ROP. Therefore,
115
AP-ROP might have specific pathophysiological features. Given that extraretinal blood vessels
116
regress spontaneously in most ROP,6 developmental retinal angiogenesis can be said to have
117
robustness in directional vascular expansion. There is no doubt that higher VEGF stimulates
118
growth of aberrant blood vessels in retina.2, 17 However, complete understanding on whether
119
increasing VEGF levels lose this robustness or not and determining the progression patterns of
120
ROP, both require further investigation.
121
stage 3+
Ultimately, it would be beneficial for ROP management to identify specific findings
122
to distinguish AP-ROP from type 1 ROP and regressed ROP in advance. In our study, we ob-
123
served blot hemorrhage on vascularized retina at the initial examination as a conspicuous retinal
124
finding. There was an increasing trend of this finding consistent with the severity of ROP sub-
125
types. However, blot hemorrhage at the initial examination was not significantly different
126
among the groups. The e-ROP study group reported that blot hemorrhage was a predictive factor
127
of ROP that required treatment.18 While blot hemorrhage at an initial exam might be a potential
128
risk factor of developing severe ROP, identification of specific findings for subtypes is still
129
challenging. Image analysis, systemic comorbidity assessment, and other technical develop-
130
ments are necessary to provide new predictive factors for ROP subtype.
131
Limitations in this study include its retrospective nature, small sample size, and all
132
cases being from a single institute. The rates of infants with any ROP and those with ROP that
133
required treatment in this study are higher than those in previous studies in the USA. To date,
134
Alaskan natives and Asians have a higher risk of developing severe ROP than do
135
Caucasians.19-21 Because ethnicity/race affects the severity of ROP, the Japanese pediatric popu-
9
136
lation might have a higher risk for developing ROP than Caucasians. With regard to disease
137
onset and the natural course of ROP, we previously reported that the median PMA at onset and
138
at treatment was 32 and 34 weeks, respectively, in infants with zone 1 ROP who were born with
139
a BW < 1250 g between 2000 and 2006.14 In the current cohort, the median PMA at onset of
140
ROP and at treatment was 31 and 34 weeks, respectively. In extremely premature infants at a
141
high risk of ROP, disease onset and the natural course have not changed for almost 2 decades in
142
our institute. Other studies from the USA and Sweden reported that the median PMA at onset
143
and stage 3 ROP were approximately 34 and 36 weeks, respectively.10, 11 Quinn et al showed
144
that onset and progression of ROP have remained stable for the last 3 decades in the USA,11
145
which is consistent with our results. However, the reason for the earlier onset and treatment in
146
our cohort still remains to be clarified. The earlier peak shift may be explained by genetic back-
147
ground and race. Moreover, the reason for onset being comparable across subtypes may be at-
148
tributed to the pathophysiology of ROP. When this disease develops, a delay in vascular growth
149
and capillary dropout at the angiogenic front are switched to outgrowth of abnormal extraretinal
150
blood vessels.17 Most infants with a GA < 27 weeks receive respiratory support and oxygen use
151
from birth.22 Therefore, an oxygen-induced delay in vascular growth and capillary dropout often
152
occur in the developing retina of these premature infants. Constriction of capillaries induces
153
excess VEGF expression, resulting in formation of extraretinal blood vessels. Increasing VEGF
154
levels can cause onset of ROP at a specific period, regardless of ROP subtypes. These possible
155
explanations for the timing of onset in our study need to be verified in future research. Addi-
156
tionally, whether the trend found in this study could be applied for other socioeconomic circum-
157
stances, other races/ethnicities, and other NICU settings is unknown.
158
A notable feature of our study is that we evaluated individual trajectories of each pa-
159
tient’s disease course among subtypes for defining characteristics of the progression pattern. In
160
management of ROP, timely and appropriate treatment is necessary to prevent visual loss.2
161
Therefore, ophthalmologists should carefully observe not to miss the therapeutic window. Our
162
findings of the ROP progression pattern by subtype in extremely premature infants could help to
10
163
perform follow-up examinations. When the onset of ROP is initially diagnosed, if the subtype
164
ends up being AP-ROP, the ROP will continues to deteriorate through the stage as seen on serial
165
examination and will likely require treatment within 1 week. If ROP develops to stage 3 after 36
166
weeks of PMA, more than half of infants achieve regression of ROP without treatment. Taken
167
together, these trends should be helpful in monitoring early disease progression and possibly
168
point towards a common pathophysiology behind the AP-ROP given the homogenous nature of
169
the individual trajectories observed in that subtype.
170 171 172 173 174
11
175
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14
232
Figure Legends
233
Figure 1. Flowchart of enrollment of the study population.
234
NICU, neonatal intensive care unit; ROP, retinopathy of prematurity; AP-ROP, aggressive pos-
235
terior retinopathy of prematurity; GA, gestational age.
236 237
Figure 2. Individual progression trajectories of infants with a GA < 27 weeks. Graphs show the
238
time to progression of ROP stages (left) and plus disease (right) in infants with AP-ROP, type 1
239
ROP, and regressed ROP. The values of plus in the vertical axis of the right panel indicate the
240
following: 1, pre-plus disease; and 2, plus disease. The endpoint of each trajectory indicates the
241
time when ROP regressed with full vascularization or progressed to the point of requiring any
242
treatment.
243
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity;
244
PMA, postmenstrual age.
245 246
Figure 3. Cumulative probability of infants who were diagnosed with stage 3 and/or plus dis-
247
ease. Kaplan–Meier failure curves show the time to progression in infants with AP-ROP, type 1
248
ROP, and regressed ROP. The horizontal and vertical dotted lines define 15% of cumulative
249
probability and 36 weeks' PMA, respectively. The PMAs when 15% of infants with AP-ROP,
250
type 1 ROP, and regressed ROP progressed to stage 3 and/or plus disease were 30.1 weeks, 32.4
251
weeks, and 38.4 weeks, respectively. Note that 95% of infants with stage 3 or plus disease by 36
252
weeks’ PMA required treatment, whereas 60% of infants with stage 3 after 36 weeks’ PMA re-
253
gressed spontaneously.
254
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity;
255
PMA, postmenstrual age.
256
1
1
Table 1. Characteristics and clinical courses of 133 premature infants
No. of patients Male gender, no. (%)
Regressed
Type 1 ROP
AP-ROP
67
43
23
33 (49.2)
16 (37.2)
10 (43.4)
BW (g)
.46 .0072
Median
654
666
564
Range
458 – 1102
394 – 1024
450 – 802
GA (weeks)
< .001
Median
25.0
25.0
23.7
Range
22.2 – 26.8
22.2 -26.7
22.5 – 25.4
PMA at initial exam (weeks)
.49
Median
29.5
29.5
29.7
Range
28.1 – 31.1
28.2 – 32.2
29.0 – 30.7
PMA at onset (weeks)
.08
Median
31.4
31.5
31.1
Range
29.2 – 42.1
29.2 -34.1
29.7 – 32.8
Duration between initial exam and onset (days)
.08
Median
14
14
9
Range
0 - 91
0 - 28
0 -14
PMA at initial treatment (weeks)
P value
< .001
2
Median
34.5
32.1
Range
31.1 – 42.2
30.0 – 35.4
Duration between onset and initial treatment (days)
< .001
Median
21
5
Range
0 - 73
0 - 17
2
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity; BW, birth weight; GA, gestational age; PMA,
3
postmenstrual age.
4 5 6 7 8 9 10
1
1
Table 2. Total number of infants screened according to PMA Regressed ROP (N = 67)
2
Type 1 ROP (N =43)
AP-ROP (N = 23)
PMA (weeks)
No. of screened patients (No. of treated patients)
< 29
4
1 (0)
0 (0)
29
49
36 (0)
15 (0)
30
60
40 (0)
23 (5)
31
66
41 (1)
18 (4)
32
66
41 (4)
14 (12)
33
63
36 (12)
2 (1)
34
60
26 (6)
1 (0)
35
55
20 (7)
1 (1)
36
53
13 (4)
0
37
44
9 (4)
0
38
49
5 (1)
0
39
43
4 (1)
0
40 ≦
64
3 (3)
0
ROP, retinopathy of prematurity; AP-ROP, aggressive posterior retinopathy of prematurity; PMA, postmenstrual age.
Précis We assessed individual trajectories across stages of retinopathy of prematurity (ROP). Aggressive posterior ROP progressed through the stages in a linear manner. In contrast, type 1 ROP and regressed ROP developed in a stepwise manner.