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Kanya Chutasmit, M.N.S., Pimol Wongsiridej, M.D. , Kanokwan Sommai, M.Sc. (Applied Statistics), Supharat
Siriwaeo, B.N.S., Pranchalee Insawang, B.N.S., Ratchada Kitsommart, M.D.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Incidence and Risk Factors of Retinopathy of
Prematurity, a 10-year Experience of a Single-center,
Referral, Hospital
ABSTRACT
Objective: To explore the incidence and trend of ROP over the past 10 years. e secondary objective was to identify
any association between clinical variables and threshold ROP.
Materials and Methods: A cross-sectional, retrospective study of infants with <33 weeks’ gestational age (GA) or
birth weight (BW) ≤1,500g were screened for ROP between January 2010 and December 2019 Infants who had
threshold ROP, labelled as the T-group, were compared against non-threshold infants (either normal or prethreshold
ROP), or the NT-group.
Results: Of the 1,247 infants who were screened for ROP, 174 (14%) tested positive for ROP while 26 (2.1%) had
threshold ROP. Infants who had ROP had a mean ±standard deviation (SD) GA 27.2 ± 2.2 weeks and 115 (66.1%)
were <1000g at birth. Advanced GA was independently associated with lower risk of threshold ROP [adjusted odds
ratio (95% condence interval, CI); 0.71 (0.52, 0.98), p=0.04]. ere was no dierence in respiratory and hemodynamic
outcomes between the T and NT-group, except for longer hospitalization (median [P25, P75]; 121[106.3, 160.5]
and 93.5[72.3, 129] days, p=0.003]. Culture-positive septicemia was independently associated with threshold ROP
[adjusted odds ratio (95% CI); 4.48 (1.72, 11.68), p=0.002].
Conclusion: e incidence of dierent stages of ROP in infants was 14% and 2.1% for severe ROP which required
treatment. Lower GA and positive-culture septicemia was associated with a higher incidence of severe ROP.
Keywords: Incidence; preterm infants; retinopathy of prematurity; screening; threshold disease (Siriraj Med J 2021;
73: 777-785)
Corresponding author: Ratchada Kitsommart
E-mail: ratchada.kit@mahidol.ac.th, rkitsommart@hotmail.com
Received 24 February 2021 Revised 30 June 2021 Accepted 30 June 2021
ORCID ID: http:orcid.org/0000-0002-7592-9899
http://dx.doi.org/10.33192/Smj.2021.101
INTRODUCTION
Retinopathy of prematurity (ROP) is the most
common cause of avoidable severe visual impairment
or blindness regardless of socioeconomic status.
1-3
is
condition has been well-documented in aecting not only
visual outcomes but also neurodevelopmental outcomes.
4,5
Multifactorial factors have been proposed as both risk
factors and preventative measures of severe ROP such as
oxygen management, transfusion practices, nutritional
and postnatal growth status, and infections. Hence, ROP
is inevitably associated with premature birth as postnatal
retinal vessel development is hastened due to postnatal
oxygen exposure and lack of placental factors to promote
normal growth of vessels, leading to an abnormal pattern
of vessels. erefore, despite improvements in perinatal
and neonatal care in a bid to minimize the amount and
duration of oxygen supplementation, retinal examinations
for ROP screening remains a mandatory strategy to
prevent severe ROP.
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While the incidence of very preterm infant birth has
increased this century, advancements in perinatal care has
provided hope in improving their associated morbidities,
including severe ROP. Eye examinations screening for
ROP require an interdisciplinary approach of pediatricians,
ophthalmologists, and caregivers. International guidelines
provide a strategy on how to screen for ROP in at-
risk preterm infants at a certain postnatal age (PNA).
6,7
Incidences of ROP vary among countries depending on
socioeconomic status and accessibility to ophthalmologic
examinations.
1
Interestingly, genetic factors have also
been proven to have an eect on ROP rates in dierent
racial groups.
8,9
Therefore, understanding the local
incidence rate of ROP is important in order to guide
strategic planning to minimize or eliminate the disease.
Unfortunately, problems related to awareness of ROP in
caregivers and a lack of experienced ophthalmologists
leads to inadequate coverage of a screening program
10
,
particularly in middle and low-income countries where
preterm infants are more likely to exposed to risk factors,
especially inadequate oxygen monitoring and oxygen
titration devices or availability of experienced caregivers
to monitor and control oxygenation throughout their
postnatal period.
We, therefore, wanted to explore incidence of ROP
from 2010 until 2019 and identify risk factors associated
with severe ROP cases.
MATERIALS AND METHODS
is was a retrospective, cross-sectional, comparative
study at the Division of Neonatology, Department of
Pediatrics, Faculty of Medicine at Siriraj Hospital, Mahidol
University, Bangkok, ailand. As a teaching and regional
tertiary referral hospital, patients in the study were both
inborn and outborn infants who ranged between low-risk
to high-risk. Preterm infants born <28 days before due
date were admitted into a one of several neonatal wards,
i.e; a neonatal intensive care unit (NICU), intermediate
care unit, or high-risk nursery, depending on birth
weight (BW) and respiratory or hemodynamic status,
regardless of primary diagnosis.An ACOG guidance for
antenatal corticosteroids administrations and intrapartum
antibiotics
11
was used throughout the study period.
We followed the International Liaison Committee of
Resuscitation (ILCOR) guideline for birth resuscitation.
12,13
Respiratory management included encouraging the use
of non-invasive ventilation (NIV) and oxygen titration
and oxygen monitoring devices were available at delivery
suites and neonatal wards. Surfactant replacement therapy
was used in infants with a clinical diagnosis of surfactant
deciency and requiring FiO
2
>0.6 (between 2013 to
2015) or >0.4 (from 2016 onwards) under NIV. Oxygen
management for preterm infants was targeted between
88%-93% until mid-2013 at which point it was changed
to 90%-95%. Nutritional management included early
parenteral nutrition within the rst few hours of life
and encouraging early trophic feeding. Human-milk
fortication was added once infants could tolerate 100
mL/kg/day feeds. Vitamin E 25 IU/day was also prescribed
aer infants were fully-fed until the 40-week PMA.
According to institutional guidelines for screening
of ROP, infants born prior to <33 weeks’ gestation or
with a birth weight ≤1,500g are required to be screened.
All eye examinations were performed under indirect
ophthalmoscopy at the bedside by- or under the direct
supervision of the pediatric ophthalmologist. The
rst examination was scheduled during the 4
th
week
of chronological age. Subsequent examinations were
scheduled over the next 1-4 weeks depending on previous
ndings and a plan of management was manually recorded
following each examination as part of a quality improvement
policy. e cases in which infants who had abnormal eye
examination reached threshold levels between January
2010 to December 2019 (the threshold, T-group) were
explored along with their associated risk factors. Each
case was selectively matched with 4 controls of normal
or pre-threshold ROP (the non-threshold, NT- group)
using the same GA strata (≤27 or >27 weeks-GA) and
admitted next to the corresponding case to minimize
selective bias from level of prematurity and variation
of general care practices over time. Infants who had
normal eye examinations were prioritized in the NT
group. However, in case there were not enough normal
controls, which occurred in the ≤27 weeks-strata, infants
who had abnormal examinations but did not meet the
criteria for threshold (pre-threshold ROP) were selected.
erefore, the NT-group consisted of both normal and
pre-threshold ROP disease. Clinical variables of eligible
infants were extracted using pre-specied outcomes by
an individual chart review for analysis.
Incidence and demographic characters were presented
as a number and percentage for categorical variables and
as mean ± standard deviation (SD) or median [percentile
25
th
(P25), percentile 75
th
(P75)]. Comparisons of infants’
clinical and ophthalmologic outcomes between groups of
gestational age (GA) ≤27 weeks and >27- weeks’ groups
was done using the Chi-square test, Fisher’s exact test,
paired t-test, and Mann-Whitney U test depending on
the type and distribution of each variable. A univariate
logistic regression analysis evaluated factors associated
with occurrence of threshold ROP using the crude odds
ratio (OR) with 95% condence interval (CI) and adjusted
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OR for signicantly dierent demographic variables with
multivariate logistic regression analysis. All statistical
analyses were performed using SPSS Statistics version
18.0 (SPSS, Inc., Chicago, IL, USA). A p-value of <0.05
was considered statistically signicant.
RESULTS
e study protocol was approved by the institutional
IRB. From January 2010 to December 2019, there were
1247 infants screened for ROP. Of these, 174 (14%)
had ROP at various stages. Our annual incidence rate
ranged from 9.2% to 24.4% (Fig 1). e mean ± standard
deviation (SD) GA of 174 infants who had abnormal eye
examinations was 27.2 ± 2.2 weeks and their mean ± SD
birth weight was 923.0 ± 257.4 g. One-hundred and een
(66.1%) infants had BW <1,000 g. One-hundred and
sixty-six (95.4%) were inborn infants, 32 (18.4%) were
small-for-gestational age and 34 (19.5%) were born from
multifetal pregnancies. reshold ROP occurred in 26
infants (2.1%) and 14.9% of infants were in the T-group
(those with ROP at dierent stages). Twenty-ve infants
had laser surgery performed, 5 received both laser surgery
and intravitreal anti-VEGF therapy, and one infant received
only anti-VEGF therapy. Of the 104 infants in the NT-
group, 31 had normal eye examinations (11 infants with
GA ≤27 weeks and 20 infants with GA >27 weeks) and
73 with prethreshold ROP (all GA ≤27 weeks). Table 1
compares baseline demographic characteristics between
the T and NT-group. Although attempts were made to
match GA, the median [P25, P75] GA of the T-group
was signicantly lower than the NT-group, 25.5 [25,
26] versus 26 [25, 27], p=0.02, and their corresponding
BW was marginally dierent (775 [707.5, 932.5] and 870
[770, 1115], respectively; p=0.05). e other baseline
characteristics were not signicantly dierent. Table 2
demonstrates clinical outcomes during hospitalization
at birth between the groups. ere were no dierences
in respiratory and hemodynamic outcomes between the
groups. However, infants in the T-group had a higher
rate of culture-positive septicemia (46.2% versus 17.3%,
p=0.004) and a longer median hospitalization stay, 121
days [106.3, 160.5] and 93.5 days [72.3, 129], p=0.003].
Among infants who had ROP at various stages,
the median [P25, P75] postnatal age (PNA) of initial
eye examination was 30 days [28, 32] at 31 [30, 33]
weeks’ postmenstrual age (PMA). e PNA of the rst
abnormal examination was 50 days [40, 58] at PMA at
34 weeks [32, 36]. Table 3 compares the characteristics
of eye examinations between the groups. PNA and PMA
of initial examinations and the rst abnormal detection
were not dierent between the groups. e T-group
had a signicantly higher number of eye examinations
during birth hospitalization (12[9, 13.3] versus 8 [5, 11.8],
respectively, p<0.001). Table 4 identies the potential risk
factors of developing threshold ROP. Culture-positive
septicemia was independently associated with threshold
ROP [adjusted OR (95%CI) 4.48 (1.72, 11.68), p =0.002]
while advanced GA was associated with lower risk of
threshold ROP [adjusted OR (95%CI) 0.71 (0.52, 0.98)
for each week, p <0.001].
Fig 2 demonstrates the proportion of ROP screening
results based on GA. e incidence trend of ROP at any
stage or at threshold were inversely high with lower GA.
(Table 5) compares characteristics of eye examinations
and the outcomes of ROP in 174 infants based on GA
strata. Infants ≤27 weeks GA had earlier both PMA for
initial eye examination and rst abnormal detection
(30 [29, 31] versus 33 [32, 34] and 33 [31, 34] versus 35
[34, 37] weeks, respectively, both p<0.001). Infants ≤27
weeks GA had a higher rate of threshold ROP (19.8%
versus 7.4%, p=0.03) and borderline dierent rates of
laser therapy (18.9% versus 7.4%, p=0.05].
Fig 1. Trend in the incidences of
retinopathy of prematurity from 2010
to 2019 (N=1,247)
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Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Gestational age (week) 25.5 [25, 26] 26 [25, 27] 0.02*
Birth weight (g) 775 [707.5, 932.5] 870 [770, 1115] 0.05
Small-for-gestational age 4 (15.4) 12 (11.5) 0.59
Large-for-gestational age 0 2 (1.9) 0.48
Inborn 25 (96.2) 102 (98.1) 0.56
Multiples 4 (15.4) 19 (18.3) 0.73
Cesarean section 10 (38.5) 67 (64.4) 0.03
Maternal complications (n =128) (n = 26) (n = 102)
Hypertension 2 (7.7) 18 (17.6) 0.36
Diabetes 3 (11.5) 12 (11.8) 1.00
Antepartum hemorrhage 3 (11.5) 4 (3.9) 0.15
Chorioamnionitis / infection 6 (23.1) 20 (19.6) 0.79
TABLE 1. Baseline demographic characteristics.
TABLE 2. Clinical characteristics during hospitalization at birth.
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Respiratory support
Non-invasive ventilation 25 (96.2) 100 (96.2) 1.00
Mechanical ventilation 25 (96.2) 88 (84.6) 0.19
Received theophylline 21 (80.8) 90 (86.5) 0.54
Surfactant administration 11 (42.3) 34 (32.7) 0.49
Pneumothorax 2 (7.7) 6 (5.8) 0.66
Bronchopulmonary dysplasia 23 (88.5) 75 (72.1) 0.13
Cardiovascular
Inotropic agent (s) 17 (65.4) 50 (48.1) 0.13
Medical ligation 15 (57.7) 58 (55.8) 1.00
Surgical ligation 7 (26.9) 31 (29.8) 0.82
Infection
Positive blood culture 12 (46.2) 18 (17.3) 0.004*
Parenteral antibiotics 26 (100) 104 (100)
GI & Nutrition
Breast milk 25 (96.2) 100 (96.2) 1.00
Pasteurized donor milk 2 (7.7) 6 (5.8) 0.66
Formula 23 (88.5) 90 (86.50 1.00
Diagnosis of NEC 8 (30.8) 40 (38.5) 0.51
Surgical NEC 0 7 (6.7) 0.34
Days of mechanical ventilation 41 [21.0 , 61.0] 30 [10.8 , 56.5] 0.21
Days of hospitalization 121 [106.3, 160.5] 93.5 [72.3, 129] 0.003*
Death during birth hospitalization 1 (3.8) 5 (4.8) 0.28
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
(Abbreviations: CPAP, continuous positive-airway pressure; CSF, cerebrospinal uid; HFNC, high-ow nasal cannula; NEC, necrotizing
enterocolitis; NIPPV, nasal intermittent positive-airway pressure)
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TABLE 3. Characteristics of eye examinations (N=130).
TABLE 4. Risk factors of threshold ROP.
Threshold Normal or
Variable disease prethreshold disease p-value
(n = 26) (n = 104)
Postnatal age of rst eye examination, day 30 [28, 32.5] 29 [27.3, 32] 0.43
Postmenstrual age of rst eye examination, week 29.5 [28.8, 32] 30 [29, 31] 0.09
Postnatal age of rst abnormal detection, day (n = 99) 50 [44, 53] 52 [44.5, 61] 0.11
Postmenstrual age of rst abnormal detection, week (n = 99) 32 [31, 34] 33 [31.5, 34] 0.16
Number of examinations during birth hospitalization 12 [9, 13.3] 8 [5, 11.8] <0.001*
Data presents as median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
Variables OR (95%CI) P-value AOR (95%CI) p-value
Gestational age
(every week increment) 0.75 (0.56, 0.99) 0.05 0.71 (0.52, 0.98) 0.04*
Birth weight
(every 100-g increment) 0.84 (0.69, 1.02) 0.07 0.95 (0.72, 1.28) 0.75
Mechanical ventilation 4.55 (0.57, 35.97) 0.15 2.42 (0.28, 21.28) 0.43
Surfactant administration 1.51 (0.63, 3.64) 0.36 1.03 (0.39, 2.72) 0.95
Days of mechanical ventilation 1.00 (0.99, 1.01) 0.33 0.99 (0.98, 1.01) 0.78
Did not receive breast milk 1.00 (0.11, 9.34) 1.00 0.68 (0.07, 6.89) 0.75
Culture-positive septicemia 4.10 (1.63, 10.31) 0.003 4.48 (1.72, 11.68) 0.002*
Medical ligation for PDA 1.08 (0.45, 2.58) 0.86 0.64 (0.24, 1.70) 0.37
Surgical ligation for PDA 0.87 (0.33, 2.27) 0.77 0.54 (0.19, 1.54) 0.25
Inotropic agents 2.04 (0.83, 4.99) 0.12 1.11 (0.41, 3.01) 0.84
AOR, adjusted odds ratio, were adjusted by gestational age and positive blood culture.
*A p-value<0.05 indicates statistical signicance.
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Fig 2. Incidences of retinopathy of prematurity by gestational age (N=1,247)
TABLE 5. Characteristics of abnormal eye examinations (N=174).
GA ≤27 weeks GA >27 weeks p-value
(n = 106) (n = 68)
PNA of rst eye examination (days) 30 [28, 33] 30 [28 ,32] 0.88
PMA of rst eye examination (weeks) 30 [29, 31] 33 [32, 34] <0.001*
PNA of rst abnormal detection (days) (n = 99) 51 [44, 59.3] 42.5 [32.3, 53.8] <0.001*
PMA age of rst abnormal detection (weeks) (n = 99) 33 [31, 34] 35 [34, 37] <0.001*
Number of examinations during hospitalization 10 [8, 13] 6 [4, 9] <0.001*
Threshold disease 21 (19.8) 5 (7.4) 0.03*
Laser therapy 20 (18.9) 5 (7.4) 0.05*
PNA of LASER therapy (days) 75.5 [66.8, 85.8] 68 [38, 88] 0.37
Intravitreous anti-VEGF therapy 5 (4.7) 1 (1.5) 0.41
PNA of anti-VEGF therapy (days) 69 [61, 108] 43 [43, 43] 0.33
Data presents as median [P25, P75] or number (percentage). *A p-value<0.05 indicates statistical signicance.
Abbreviations: PMA, postmenstrual age; PNA, postnatal age; VEGF, vascular endothelial growth factor
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DISCUSSION
Retinopathy of prematurity (ROP) remains an important
morbidity factor in extremely preterm infants. Since its risk
is the result of premature birth, total elimination of ROP
remains a challenge even though various strategies have
been attempted to minimize the risk of the disease. In fact,
a standard screening program is mandatory to explore the
magnitude of the disease and, more importantly, to identify
early abnormal vessels to allow for early management
that can save an infant’s long-term vision. Relatively
recent reports about incidence of ROP at any stage of
the disease ranges between 9% to 27%.
14-17
However, it is
a challenge to compare results because such a big range
of incidence can be explained by a few possibilities. e
rst, and most important reason, is the availability to
provide care for very premature infants and associated
risk factors. Middle-income countries especially have a
high burden of ROP due to improvements in survival
rate of extremely premature infants, however, they still
have limited resources to monitor and titration of oxygen
devices.
1
is phenomenon has been noted aer studies
have revealed the incidence of ROP in middle-income
countries was as high as 69% in extremely-low birthweight
infants.
18
Second, criteria for ROP screening suggested
from dierent expertise groups are not uniform, mainly
included GA and BW.
6,19
Generally, ROP screening is
suggested for infants with GA ≤30 or 32 weeks or a BW
of ≤1,500 g. Although we perform screening for all <33
weeks’ gestation or ≤1,500 g BW infants, only 7 out of
130 (5.4%) who were 31 to 32 weeks’ GA and had BW
>1,500 g. So, proportion of at-risk infants who were
screened overall should be comparable to the other reported
incidence using minor dierent criterion. ird, various
denitions of severe ROP were selected in each report
and used treatment requiring ROP or threshold ROP to
represent the severity. Our incidence of ROP at any stage
of the disease was 14%, which was relatively low when
compared to other upper middle-income countries where
the incidence ranges between 19% to 33%.
17,20,21
In fact, our
incidence showed ROP rates decreased from 2010 to 2013.
However, there was a sharp increase in ROP rate from
9.3% in 2013 to 14.3% in 2014. We suspect this rise was
secondary due to changes of targeted oxygen saturation
which was reported in a previous study.
22,23
However,
our incidence of threshold ROP at 2.1% was relatively
stable throughout the study period and comparable to
the other reports from developed countries.
14
Timing of abnormal neovascularization usually found
during vasoproliferative phase of ROP.
19,24
We found
median PNA of initial abnormal vessels detection were
50 days in threshold ROP and 52 days for prethreshold
ROP which were correspondence to 32- and 33-weeks
PMA. Since their PNA and PMA were comparable
between the groups, timing of initial abnormal detection
cannot predict their subsequent results of abnormal
vessels which emphasize the importance of subsequent
follow-up examinations until full development of retinal
vessels.
Observational studies have shown several risk factors
associated with either ROP at various stages of disease
progression or threshold ROP. e most potent risk of
baseline characteristics is premature birth,
10,14,25
which
was also demonstrated in our study [adjusted OR 0.71
(0.52, 0.98), p=0.04]. Although 66.1% of ROP cases in
our study were extremely premature infants (birth weight
<1,000 g), we did not nd any signicant association
between BW and threshold ROP. So, premature birth
is a more potent risk factor than intrauterine growth.
Dysoxemia and clinical unstable are proposed to be
at-risk for ROP.
26-29
We did not nd any dierences
in respiratory outcomes such as intubation, duration
of mechanical ventilation, surfactant administration,
pneumothorax, or bronchopulmonary dysplasia or in
hemodynamic parameters (inotropic agents or treatment
of patent ductus arteriosus) in infants with threshold
ROP and the control group. Postnatal nutrition plays
an important role on normal retinal vessels via optimal
level of IGF-1 and antioxidative factors in breast milk.
30
Hence, we did not nd dierent rate of threshold ROP in
infants who received maternal breast milk or pasteurized
donor milk (PDM [adjusted OR 0.68 (0.07, 6.89), p=0.75].
However, due to the limited number of infants who did
not receive breast milk, this phenomenon is deserved to
be explored further with adequate sample size.
e meta-analysis showed signicant association
between chorioamnionitis and severe ROP,
31
but no study
has found a similar association for postnatal septicemia.
Interestingly, we noticed positive-culture septicemia as
a risk factor [adjusted OR 4.48 (1.72, 11.68), p=0.002].
e possibility of this relationship can be attributed to
inammation cascade suppressed early retinal vascularization
and cause severe neovascularization later or secondary to
systemic instability during sepsis contributed to retinal
hypoxia and develop ROP later.
32
We reported our incidence rate in a large number
of at-risk infants from the tertiary care referral center in
ailand where the ROP screening program, including
patient selections, examination maneuvers and recording,
follow-up practices and therapy is already established.
All eye examinations were interpreted by only one
pediatric ophthalmologist which ensured internal validity.
However, some limitations must be considered. First,
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due to our cross-sectional design, we could not ensure
timely association or if some variables occurred before
or aer detection of abnormal retinal vessels. erefore,
our results assumed association between these variables
and ROP occurrence. Hence, PNA of abnormal ndings
occurred around 50 days when most clinical stability was
already established or had subsided. is was assumed to
occur before any ndings of ROP. Second, our patients
were mainly inborn infants where physicians, caregivers,
devices, and monitoring equipment were available. Our
incidence rate may not reect the true incidence rate in
the country, especially in rural areas where resources are
limited, especially in coverage of the screening program.
CONCLUSION
In conclusion, during the past 10 years, our incidence
of ROP at any stage in infants born <33 weeks or with
a BW <1,500 g was 14% and 2.1% for threshold ROP
requiring treatment. Lower GA and positive-culture
septicemia were found to be associated with occurrence
of threshold ROP.
ACKNOWLEDGEMENTS
We gratefully give thanks to Professor La-Ongsri
Atchaneeyasakul for her contribution in performing eye
examination throughout the study period.
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