Nationwide Incidence of Infantile Cataract

Surgery and Risk of Secondary Glaucoma in a

Population-based Birth Cohort

SOOYEON CHOE, AHNUL HA#, SEULGGIE CHOI, SUNG UK BAEK, JIN-SOO KIM, JIN WOOK JEOUNG,
KI HO PARK, AND YOUNG KOOK KIM#

• PURPOSE: To determine the nationwide birth cohort IC surgery glaucoma risk other than primary or secondary
incidence of infantile cataract (IC) surgery and the risk intraocular lens implantation, which reduces the risk (all
of secondary glaucoma in a Korean population. P < .05). In patients without primary intraocular lens
• DESIGN: A population-based, retrospective cohort implantation, the risk of glaucoma increased steeply dur-
study. ing the first 2 years after IC surgery.
• METHODS: We accessed the Korean National Health • CONCLUSION: This study identified the birth cohort
Claims database to identify patients with IC who were incidence of IC surgery and secondary glaucoma risk
diagnosed before 1 year of age and who underwent IC in individuals of East Asian ethnicity. These estimates
surgery among all Koreans born between 2008 and 2018 may help to better understand the epidemiologic features
(n = 9,593,003). We estimated IC surgery incidence in a and clinical courses of patients with IC.</ABSTRACT>
birth cohort. The incidence rates of post–IC surgery glau- (Am J Ophthalmol 2023;246: 130–140. © 2022 Elsevier
coma were estimated per 100 person-years, based on the Inc. All rights reserved.)
Poisson distribution. The risk factors for post–IC surgery
glaucoma, including ophthalmic and systemic comorbidi-

I
ties, were analyzed by multivariable logistic regression nfantile cataract (IC) refers to lens opacity oc-
analysis. curring within the first year of life. With an estimated
• RESULTS: During the 11-year study period, 692 pa- prevalence of 1 to 6 cases per 10,000 live births,1 , 2 IC
tients underwent IC surgery. The annual birth cohort in- covers a broad spectrum of severity: whereas some lens
cidence of IC surgery in the general population ranged opacities do not progress, others can affect profound visual
from 5.10 to 9.29 cases per 100,000 individuals. Among impairment. For optimal visual development in newborns
patients who had been followed up for longer than 1 year and young infants, visually significant IC should be detected
(n = 650), 92 (14.2%) developed glaucoma, and its in- as early as possible and surgically removed.3 , 4
cidence rate was 2.29 (95% confidence interval, 1.86- Despite the strides made in IC management, secondary
2.80) per 100 person-years. The mean time from IC glaucoma is still a major sight-threatening complication
surgery to glaucoma development was 4.7 ± 3.5 years. postoperatively.5 , 6 Although the pathogenesis of post–IC
No factors were identified as being associated with post– surgery glaucoma remains unclear, observational studies
and randomized clinical trials (RCTs) have identified the
following risk factors: young age at IC surgery,7 , 8 apha-
Supplemental Material available at AJO.com. kic state after IC surgery,8 residual lens epithelial cells,9 , 10
Accepted for publication October 18, 2022. persistent hyperplastic primary vitreous,11 primary poste-
From the Department of Ophthalmology (S.Choe, J.W.J., K.H.P., rior capsulotomy,12 microphthalmia,10 , 13 and trypan blue
Y.K.K.), Seoul National University College of Medicine, Seoul; De-
partments of Ophthalmology (S.Choe, J.W.J., K.H.P., Y.K.K.), Seoul Na- usage.14 However, whether these factors increase the risk
tional University Hospital, Seoul; Internal Medicine (S. Choi), Seoul of post–IC surgery glaucoma remains controversial because
National University Hospital, Seoul; Departments of Ophthalmology of residual confounding from selection biases in observa-
at Jeju National University Hospital and Jeju National University Col-
lege of Medicine (A.H.); Jeju-si; Departments of Ophthalmology at Hal- tional studies as well as the impossibility of including large
lym University College of Medicine, Chuncheon; Hallym University Sa- unselected patient populations in RCTs. Also, the reported
cred Heart Hospital (S.U.B.), Anyang; Department of Ophthalmology incidence of post–IC surgery glaucoma varies widely, from
(J-S.K.), Chungnam National University Sejong Hospital, Sejong; De-
partment of Pediatric Ophthalmology (Y.K.K.), Seoul National University 6% to 59%, depending on the study design and follow-up
Children’s Hospital, Seoul; EyeLight Data Science Laboratory (Y.K.K.), period.8 , 14–22
Seoul, Korea In this context, we conducted a nationwide, population-
Correspondence: Young Kook Kim, Department of Pediatric Ophthal-
mology, Seoul National University Children’s Hospital, 101 Daehak-ro,
based birth cohort study using the Korean National Health
Jongno-gu, Seoul 03080, Republic of Korea; e-mail: [email protected] Claims database compiled by the mandatory universal
Correspondence: Ahnul Ha, Department of Ophthalmology, Jeju Na- health insurance system in South Korea. We investigated
tional University Hospital, 15, Aran 13-gil, Jeju-si, Jeju-do, 61241, Re-
public of Korea; e-mail: [email protected]
1) the real-world birth cohort incidence of IC surgery, 2)
# Drs Ha and Kim served jointly as corresponding authors. the risk of secondary glaucoma after IC surgery, and (3)

130 © 2022 ELSEVIER INC. ALL RIGHTS RESERVED. 0002-9394/$36.00

https://doi.org/10.1016/j.ajo.2022.10.015
ocular and systemic factors associated with post–IC surgery cluded, from the 2019 database, those with <1 year of
glaucoma development. follow-up after IC surgery. Among all South Korean chil-
dren born between 2008 and 2018 (n = 9,593,003), those
who had been diagnosed with IC were identified. To filter
out cases where the IC diagnosis code had been entered in-
METHODS correctly (ie, cases in which acquired cataracts had been
misclassified as ICs), we limited our selections to those di-
This nationwide, population-based, retrospective cohort agnosed with IC before the age of 1 year and on whom IC
study was conducted based on a prespecified protocol.23 surgery subsequently was performed. Accordingly, to enroll
Approval of Institutional Review Board of Seoul National only patients with post–IC surgery glaucoma, the following
University Hospital was obtained. The study adhered to the cases among those with the glaucoma diagnosis code (H40)
tenets of the Declaration of Helsinki. Informed consent was were excluded: (1) glaucoma diagnosis before IC surgery,
waived because of the retrospective use of anonymous data. (2) administration of antiglaucoma medication before IC
surgery, and (3) <1 year of follow-up after IC surgery. Fi-
• KOREAN NATIONWIDE EPIDEMIOLOGICAL STUDY FOR nally, selected patients were classified according to whether
CHILDHOOD GLAUCOMA: This study is part of the Korean they had been administered an antiglaucoma agent for >3
Nationwide Epidemiological Study for Childhood Glau- months or undergone glaucoma surgery after IC surgery,
coma, which plans for a nationwide epidemiologic study into 2 groups: (1) patients with post–IC surgery glaucoma
of both primary glaucoma (ie, primary congenital glau- and (2) those without post–IC surgery glaucoma (Figure 1).
coma, juvenile open-angle glaucoma) and secondary glau- For bilateral IC cases, we defined the earlier date of glau-
coma (ie, Sturge-Weber syndrome–associated glaucoma, coma conversion as the date of glaucoma development.
steroid-induced glaucoma, postoperative glaucoma) in Ko-
rean children. We have registered this project’s proto-
col in the Open Science Framework (registration number • STATISTICAL ANALYSES: We defined a group of children
doi:10.17605/OSF.IO/AWTEC). born during a particular year as a birth-year cohort. The
birth cohort incidence of IC surgery was calculated as the
• DATA SOURCES AND DATA COLLECTION: We accessed number of patients having had IC surgery divided by the
the Health Insurance Review and Assessment (HIRA) general population ≤1 year of age. To determine the to-
database between 2007 and 2019. HIRA is an independent tal age-less-than-1-year population of South Korea, Pop-
government-operated organization that evaluates medical ulation and Housing Census data (Korean Statistical In-
claims data. South Korea has a mandatory public health formation Service; available at: http://kosis.kr) were used.
insurance coverage system, and HIRA covers almost When a patient underwent multiple surgeries, the estimate
50 million people, representing about 98% of the total was based on the first surgery. The incidence rate of post–IC
population.24 surgery glaucoma along with the 95% confidence intervals
HIRA holds all medical claim–related data on demo- (CIs) was estimated per 100 person-years. The 95% CI of
graphics, diagnoses, medical appointments, procedures, pre- the incidence rates were determined with the Poisson re-
scriptions, and comorbidities for the entire population of gression model. Kaplan-Meier survival analysis was used to
South Korea.25 , 26 The diagnoses therein are coded from the plot the probability curves of the development of post–IC
Korean Standard Classification of Diseases, 7th revision, which surgery glaucoma. Log-rank testing subsequently was per-
is the International Classification of Diseases, 10th revision, as formed to compare the Kaplan-Meier survival curves by sex
amended to fit the Korean context. For the present study, and surgery group (ie, IC surgery without IOL implanta-
patients with IC were extracted based on the Q12.0 diag- tion, IC surgery with primary IOL implantation, and IC
nostic code. IC surgeries included cataract and lens extrac- surgery with secondary IOL implantation). To investigate
tion surgeries (S5110-S5112, S5119), secondary intraocu- the risk factors of post–IC surgery glaucoma, a case-control
lar lens (IOL) implantation (S5116), and primary IOL im- study was nested into the cohort. Cases were members of the
plantation (S5117). In addition, the potential risk factors cohort who had developed post–IC surgery glaucoma. For
for post–IC surgery glaucoma (ie, demographics, treatment each case, 3 randomly selected control subjects from the co-
patterns, comorbidities, and ophthalmic anomalies) were hort were matched for year at the time of the first IC surgery.
obtained (Table 1). The method regarding our use of spe- With these matched case controls, a multivariable analysis
cific diagnostic codes for genetic and metabolic comorbidi- of the risk factors was performed by logistic regression.
ties, infectious diseases, and ophthalmic anomalies is de- All statistical analyses were performed with SAS Enter-
scribed in detail in the Supplemental Material. prise Guide software (version 7.1; SAS Inc, Cary, North
Carolina, USA). Except where otherwise stated, the data
• STUDY SUBJECTS: After excluding those with glaucoma are presented as mean ± standard deviation, the level of
codes in 2007, we determined the patients with newly di- statistical significance set at 2-sided P < .05. P values were
agnosed glaucoma for the years 2008-2018. Further, we ex- calculated using the Wilcoxon rank sum test for continu-

VOL. 246 INFANTILE CATARACT SURGERY AND SECONDARY GLAUCOMA 131

 TABLE 1. Demographics and Clinical Characteristics

Characteristics Patients With IC Surgery (N = 692)

Age at index date, n (%)

0 to ≤28 days 100 (14.5)
>28 days to ≤1 year 592 (85.6)
Age at IC surgery, n (%)
0 to ≤28 days 49 (7.1)
>28 days to ≤1 year 605 (87.4)
>1 year to ≤2 years 26 (3.8)
≥3 years 12 (1.7)
Sex, n (%)
Male 366 (52.9)
Female 327 (47.3)
Laterality of IC, n (%)
Unilateral 274 (39.6)
Bilateral 418 (60.4)
Simultaneous IC surgery, n (%)
One eye surgery 363 (52.5)
Both eye surgery 329 (47.5)
Type of IC surgery, n (%)
Aphakia 223 (32.2)
Primary IOL implantation 210 (30.4)
Secondary IOL implantation 259 (37.4)
Time from diagnosis to IC surgery (days),
mean ± SD (median [IQR]) 72.9 ± 222.6 (12 [4-31])
Type of medical institution, n (%)
Tertiary hospital 642 (92.8)
General hospital 50 (7.2)
Comorbidities, n (%)
Genetic and metabolic
Down syndrome 7 (1.0)
Hallermann-Streiff syndrome 2 (0.3)
Lowe syndrome 23 (3.3)
Galactosemia 2 (0.3)
Marfan syndrome 0 (0.0)
Trisomy 13-15 1 (0.1)
Neonatal hypoglycemia 12 (1.7)
Alport syndrome 2 (0.3)
Myotonic dystrophy 1 (0.1)
Fabry disease 0 (0.0)
Hypoparathyroidism 0 (0.0)
Conradi-Hunermann syndrome 2 (0.3)
Incontinentia pigmenti 0 (0.0)
Infections
Toxoplasmosis 16 (2.3)
Coxsackievirus 0 (0.0)
Syphilis 3 (0.4)
Varicella zoster 0 (0.0)
HIV 0 (0.0)
Parvo B19 0 (0.0)
Rubella 0 (0.0)
Cytomegalovirus 13 (1.9)
Ophthalmic anomalies
Congenital malformations of anterior segment 15 (2.2)
Microphthalmia 26 (3.8)
Persistent fetal vasculature 48 (6.9)
Congenital malformation of retina 3 (0.4)

HIV = human immunodeficiency virus; IC = infantile cataract; IOL = intraocular lens;

IQR = interquartile range; SD = standard deviation.

132 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2023

FIGURE 1. Flowchart of study subjects. IC = infantile cataract.

ous variables and the χ 2 or Fisher exact test for categorical population (per 100,000) was 9.29 (95% CI 7.32-11.25) in
variables. 2008 and 6.09 (95% CI 4.80-8.58) in 2018; that in boys
ranged from 8.59 (95% CI 5.96-11.22) in 2008 to 4.88
(95% CI 2.63-7.14) in 2018 and in girls ranged from 10.03
(95% CI 7.10-12.96) in 2008 to 8.60 (95% CI 5.52-11.68)
RESULTS in 2018 (Table 2).

• STUDY PARTICIPANTS: During the 11-year observa-

tional period (average 6.2 years), 4611 children born • INCIDENCE OF POST–IC SURGERY GLAUCOMA: Among
between 2008 and 2018 had a diagnosis code for IC in 692 patients with IC surgery, 650 (93.9%) with ≥1 year of
the HIRA database. Among them, 692 patients who had follow-up after IC surgery were included for post–IC surgery
first been diagnosed with IC before 1 year of age and glaucoma incidence estimation. During the post–IC surgery
subsequently underwent IC surgery were included in the observational period, secondary glaucoma occurred in 92 of
estimates (Figure 1). One hundred (100) patients were 650 patients (14.1%), comprising 47 male patients and 45
diagnosed before 1 month of age, and 592 patients were female patients. The mean (standard deviation) time to de-
diagnosed after 1 month and before 1 year of age. Three velopment of post–IC surgery glaucoma was 4.7 (3.5) years.
hundred sixty-six (366) patients (52.9%) were male and The annual birth-cohort incidence of post–IC surgery glau-
418 (60.4%) were cases with bilateral IC. The IC surgeries coma was 2.29 (95% CI 1.86-2.80) per 100 person-years. In
were performed 2.43 ± 7.42 months from the initial diag- male patients, the incidence was 2.25 (95% CI 1.69-3.00)
nosis, and the majority (92.8%) were performed in tertiary per 100 person-years, and in female patients 2.32 (95%
hospitals (Table 1). CI 1.73-3.10) per 100 person-years (P = .892; Table 3).
A graph of cumulative birth-cohort incidence of post–IC
• BIRTH-COHORT INCIDENCE OF IC SURGERY: The an- surgery glaucoma is shown in Figure 2. As indicated, the
nual birth-cohort incidence of IC surgery in the general risk of glaucoma steadily increased for ≥11 years after IC

VOL. 246 INFANTILE CATARACT SURGERY AND SECONDARY GLAUCOMA 133

 TABLE 2. Birth Cohort Incidence of Infantile Cataract Surgery (Per 100,000 Population)

Year Total Male Female P Value

Bir th Cohor t IC Surgery Incidence (95% CI)a Bir th Cohor t IC Surgery Incidence(95% CI)a Bir th Cohor t IC Surgery Incidence(95% CI)a
Population Cases Population Cases Population Cases

2008 926,140 86 9.29 (7.32-11.25) 477,355 41 8.59 (5.96-11.22) 448,785 45 10.03 (7.10-12.96) .473
2009 912,365 68 7.45 (5.68-9.22) 469,816 34 7.24 (4.80-9.67) 442,550 34 7.68 (5.10-10.27) .805
2010 890,570 65 7.30 (5.52-9.07) 458,990 33 7.19 (4.74-9.64) 431,580 32 7.41 (4.85-9.98) .901
2011 907,017 70 7.72 (5.91-9.53) 467,351 39 8.34 (5.73-10.96) 439,666 31 7.05 (4.57-9.53) .484
2012 929,126 80 8.61 (6.72-10.50) 477,803 41 8.58 (5.95-11.21) 451,324 39 8.64 (5.93-11.35) .985
2013 922,292 47 5.10 (3.64-6.55) 473,569 28 5.91 (3.72-8.10) 448,723 19 4.23 (2.33-6.14) .261
2014 883,293 56 6.34 (4.68-8.00) 453,145 28 6.18 (3.89-8.47) 430,149 28 6.51 (4.10-8.92) .846
2015 860,513 61 7.09 (5.31-8.87) 441,249 41 9.29 (6.45-12.14) 419,264 20 4.77 (2.68-6.86) .015
2016 848,887 57 6.71 (4.97-8.46) 435,150 33 7.58 (5.00-10.17) 413,737 24 5.80 (3.48-8.12) .318
2017 795,416 54 6.79 (4.98-6.80) 407,964 30 7.35 (4.72-9.99) 387,452 24 6.19 (3.72-8.67) .531
2018 717,386 48 6.69 (4.80-8.58) 368,520 18 4.88 (2.63-7.14) 348,866 30 8.60 (5.52-11.68) .058

CI = confidence interval; IC = infantile cataract.

a
95% CI for the incidence was estimated using a Poisson regression model.

TABLE 3. Incidence of Post–Infantile Cataract Surgery Glaucoma (Per 100 Person-Years)

IC Surgery Patients, n (%) Follow-up Duration (Years), Sum/Mean ± SD,(Median [IQR]) Glaucoma Patients, n (%) Incidence(95% CI)a P Value

Total 650 (100) 4026/6.2 ± 3.2 (6.2 [3.5-9.0]) 92 (14.1) 2.29 (1.86-2.80)
Male 340 (52.3) 2085/6.13 ± 3.2 (6.2 [3.5-8.9]) 47 (13.8) 2.25 (1.69-3.00) .892
Female 310 (47.8) 1941/6.27 ± 3.3 (6.3 [3.5-9.2]) 45 (14.5) 2.32 (1.73-3.10)

CI = confidence interval; IC = infantile cataract; IQR = interquartile range; SD = standard deviation.

a
95% CI for the incidence was estimated using a Poisson regression model.

surgery (Figure 2, A). There were no statistical differences glaucoma after congenital cataract surgery during the study
in cumulative incidence of glaucoma by sex (P = .987; period. Cumulative incidence was significantly different
Figure 2, B). among the 3 surgical techniques (P < .001 by log-rank
test). Group 1 (IC surgery without IOL implantation)
• NESTED CASE-CONTROL MATCHING FOR RISK FACTOR showed the highest cumulative incidence and group 2
EVALUATION: In a random 1:3 case-control matching pro- (IC surgery with primary IOL implantation) showed the
cess, 92 cases and 276 control subjects were selected lowest incidence. In group 1, the risk of glaucoma increased
(Table 4). Compared with control subjects, patients had steeply during the first 2 years after IC surgery and then
no statistical difference in age at IC diagnosis, age at IC slowly increased.
surgery, or laterality of IC surgery (all P > .05). Also, there
were no significant differences in the presence or absence
of ophthalmic anomalies, genetic and metabolic diseases,
or infectious diseases (all P > .05). DISCUSSION
• FACTORS ASSOCIATED WITH POST–IC SURGERY GLAU- To our knowledge, this is the first nationwide, population-
COMA RISK: In the multivariable analysis, genetic, based study to investigate the birth cohort incidence of IC
metabolic, and infectious comorbidities were not asso- surgery and the risk of secondary glaucoma. Post–IC surgery
ciated with a risk of post–IC surgery glaucoma (Table 5). glaucoma occurred in 92 of 650 cases (14.2%) in the aver-
However, cataract surgery without IOL implantation age 6.2-year period, and the mean time from IC surgery to
showed a significantly higher occurrence of post–IC glaucoma development was 4.7 years.
surgery glaucoma than IC surgery with IOL implantation Previous reports with similar follow-up periods have indi-
(all P < .05). Figure 3 plots the development of secondary cated that the incidence rates of glaucoma after IC surgery

134 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2023

 TABLE 4. Comparison of Demographics and Clinical Characteristics Between Cases and Control Subjects

Characteristics Cases(Patients WithPost–IC Control Subjectsa P Value

Surgery Glaucoma), n = 92 (Patients Without Post–IC Surgery
Glaucoma), n = 276
Sex, n (%) .718b
Male 47 (51.1) 147 (53.3)
Female 45 (48.9) 129 (46.7)
Age at diagnosis, n (%) .077b
0 to ≤28 days 21 (22.8) 41 (14.9)
>28 days to ≤1 year 71 (77.2) 235 (85.1)
Age at IC surgery, n (%) .103b
0 to ≤28 days 8 (8.7) 21 (7.6)
>28 days to ≤1 year 84 (91.3) 242 (87.7)
≥1 year 0 (0.0) 13 (4.7)
Laterality of IC, n (%) .060b
Unilateral 18 (19.6) 82 (29.7)
Bilateral 74 (80.4) 194 (70.3)
Simultaneous IC surgery, n (%) 1.000b
One eye surgery 28 (30.4) 84 (30.4)
Both eye surgery 64 (69.6) 192 (69.6)
Type of IC surgery, n (%) <.001b
Aphakia 39 (42.4) 64 (23.2)
Primary IOL implantation 9 (9.8) 95 (34.4)
Secondary IOL implantation 44 (47.8) 117 (42.4)
Duration from IC surgery to secondary glaucoma (years) 4.7 ± 3.5
(4.3 [1.5-7.4])
Follow-up duration from diagnosis to end of study (years) 7.9 ± 3.0 7.8 ± 2.9 .774d
(8.1 [5.6-10.7]) (8.2 [5.6-10.3])
Institution of IC surgery, n (%)
Type of medical institution .023b
Tertiary hospital 81 (88.0) 262 (94.9)
General hospital 11 (12.0) 14 (5.1)
Location of medical institution 1.000c
City 91 (98.9) 273 (98.9)
Rural 1 (1.1) 3 (1.1)
Comorbidities, n (%)
Genetic and metabolic diseases 6 (6.5) 23 (8.3) .577b
Down syndrome 0 (0.0) 5 (1.8) .337c
Hallermann-Streiff syndrome 0 (0.0) 1 (0.4) 1.000c
Lowe syndrome 5 (5.4) 9 (3.3) .352c
Galactosemia 1 (1.1) 0 (0.0) .250c
Marfan syndrome 0 (0.0) 0 (0.0)
Trisomy 13-15 0 (0.0) 0 (0.0)
Neonatal hypoglycemia 0 (0.0) 8 (2.9) .209c
Alport syndrome 0 (0.0) 0 (0.0)
Myotonic dystrophy 0 (0.0) 0 (0.0)
Fabry disease 0 (0.0) 0 (0.0)
Hypoparathyroidism 0 (0.0) 0 (0.0)
Conradi-hunermann syndrome 0 (0.0) 0 (0.0)
Incontinentia pigmenti 0 (0.0) 0 (0.0)
Infectious diseases 3 (3.3) 19 (6.9) .204b
Toxoplasmosis 3 (3.3) 12 (4.4) .770c
Coxackievirus 0 (0.0) 0 (0.0)
Syphilis 0 (0.0) 3 (1.1) .576c
Varicella-Zoster 0 (0.0) 0 (0.0)
HIV 0 (0.0) 0 (0.0)
Parvo B19 0 (0.0) 0 (0.0)
Rubella 0 (0.0) 0 (0.0)
Cytomegalovirus 0 (0.0) 6 (2.2) .343c
Ophthalmic anomalies 13 (14.1) 25 (9.1) .166b
Congenital malformations of anterior segment 4 (4.4) 4 (1.5) .111c
Microphthalmia 5 (5.4) 9 (3.3) .352c
Persistent fetal vasculature 5 (5.4) 13 (4.7) .782c
Congenital malformation of retina 0 (0.0) 1 (0.4) 1.000c

HIV = human immunodeficiency virus; IC = infantile cataract; IOL = intraocular lens.

a
For each case, 3 randomly selected control subjects from the cohort were matched for year at the time of the first IC surgery.
b
P values were calculated using χ 2 test.
c
P values were calculated using the Fisher exact test.
d
P values were calculated using the Wilcoxon rank sum test.

VOL. 246 INFANTILE CATARACT SURGERY AND SECONDARY GLAUCOMA 135

FIGURE 2. Cumulative incidence graph of patients with post–infantile cataract surgery glaucoma. A. Cumulative incidence graph
of total population. Post–infantile cataract surgery glaucoma occurred abruptly 1 year after infantile cataract surgery. B. Cumulative
incidence graph by sex. There were no significant male/female differences (P = .987).

were 12% (in the IoLunder2 study) from the United King- It is noteworthy that primary IOL implantation de-
dom and Ireland,27 17% (in the Infant Aphakia Treatment creased the risk for post–IC surgery glaucoma in this study,
Study [IATS]) from the United States,18 and 14% (in a even after taking age at diagnosis and microphthalmia
RCT) from India.28 Mataftsi and associates20 reported that, into account. There have been contradictory results on
based on a meta-analysis of individual patient data, 17% of the question of whether primary IOL implantation lowers
patients were diagnosed with glaucoma after IC surgery dur- the occurrence of post–IC surgery glaucoma. The previous
ing an average 4.3 years of follow-up. RCTs, the IATS29 and a study by Vasavada and associates,28

136 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2023

 TABLE 5. Univariable and Multivariable Logistic Regression Analyses of Matched Cohort

Univariable Analysis Multivariable Analysisa

Characteristics
OR (95% CI) P Value OR (95% CI) P Value

Sex
Male 1
Female 1.09 (0.68-1.74) .720
Age at diagnosis
0 to ≤28 days 1 1
>28 days to ≤1 year 0.56 (0.30-1.04) .066 0.80 (0.40-1.59) .522
Age at IC surgery
0 to ≤28 days 1
>28 days to ≤1 year 0.86 (0.35-2.14) .753
≥1 year <0.001 (<0.001->999.999) .989
Type of IC surgery
Aphakia 1 1
Primary IOL implantation 0.13 (0.05-0.30) <.001 0.08 (0.03-0.21) <.001
Secondary IOL implantation 0.63 (0.36-1.12) .117 0.27 (0.12-0.61) .002
Location of institution
City 1
Rural 1.00 (0.10-9.61) 1.000
Comorbidities (reference = 1)
Genetic and metabolic 1.32 (0.51-3.45) .565
Infections 2.37 (0.65-8.68) .192 2.32 (0.67-9.51) .243
Ophthalmic anomalies 0.59 (0.28-1.24) .161 0.80 (0.35-1.87) .611
Microphthalmia 1.67 (0.55-5.10) .370

CI = confidence interval; IC = infantile cataract; IOL = intraocular lens; OR = odds ratio.

The association between baseline characteristics and secondary glaucoma was estimated using
conditional logistic regression model in cases and controls (1:3 matching).
a
Variables with statistically significant associations (P < .2) on univariable analysis were included
in a multivariable conditional logistic regression model.

reported that primary IOL implantation did not reduce mechanical—the absence of mechanical support for the tra-
glaucoma risk. Since those 2 studies noted above involved becular meshwork in aphakic eyes may result in structural
only 26 and 15 glaucoma eyes, respectively, there are damage to it. This could reduce outflow of aqueous humor,
concerns that those small event sizes may have contributed leading eventually to the development of glaucoma.
to underestimation of the significance of the independent In addition, we performed a subgroup analysis of bilat-
variable. On the other hand, our analysis using a nation- eral IC cases, since the difference between unilateral and
wide, population-based cohort design, which has a larger bilateral is potentially correlated with age at IC surgery,
sample size, demonstrated that primary IOL implantation type of IC surgery, and comorbid systemic and ocular ab-
is a protective factor regarding glaucoma development. normalities. Supplemental Table 1 reveals that IC surgery
This result is in line with a meta-analysis report by Zhang without IOL implantation (ie, aphakia) carries a higher
and associates30 and a report from the PEDIG registry.8 risk of developing glaucoma than does IC surgery with IOL
The contrasting results between small-sized RCTs and implantation (P < .001). Supplemental Figure 1 plots a
larger-sized studies emphasize the need for further RCTs cumulative incidence curve that shows the highest risk of
with larger event sizes. glaucoma in group 1 (IC surgery without IOL implantation)
Potential mechanisms accounting for the protective ef- and the lowest risk in group 2 (IC surgery with primary IOL
fect of primary IOL implantation respecting the develop- implantation; P < .001 by log-rank test). This is consistent
ment of post–IC surgery glaucoma can be referenced in a with the overall results shown in Table 5 and Figure 3.
previous report by Asrani and associates.31 The first theory In the present study, the mean time from IC surgery to
is chemical—in aphakic eyes, the vitreous, which is toxic the development of glaucoma was 4.7 years. Twenty-five
to the trabecular meshwork, may prolapse into the ante- percent (25%) of patients with glaucoma were diagnosed
rior chamber and contact the trabecular meshwork, lead- within 1.5 years after IC surgery, 50% of patients with sec-
ing to chemical damage to the latter. The second theory is ondary glaucoma within 4.2 years, and 75% of patients with

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FIGURE 3. Cumulative incidence graph of patients with post–infantile cataract (IC) surgery glaucoma by surgery group. Group 1
included patients with IC surgery without intraocular lens implantation; group 2 included patients with IC surgery with primary
intraocular lens implantation; and group 3 included patients with IC surgery with secondary intraocular lens implantation. Cumula-
tive incidence significantly differed among the 3 surgical techniques (P < .001). Group 1 showed the highest cumulative incidence
and group 2 showed the lowest cumulative incidence. In group 1, the risk of glaucoma development was especially high in the first
2 years after IC surgery.

glaucoma within 7.3 years. In the IATS,29 risk of glaucoma the HIRA database, some patients with ocular hypertension
increased from 17% at 5 years to 22% at 10 years. As the without optic nerve changes who were prescribed antiglau-
risk of glaucoma continues for ≥7 years after IC surgery, pa- coma agents for >3 months may have been included, the
tients undergoing IC surgery should be closely monitored inclusion of which could have contributed to an overes-
for glaucoma in childhood and beyond. timation of the glaucoma incidence rate. Fourth, patients
who had undergone IC surgery outside of Korea would have
• LIMITATIONS: Our study has several limitations. First, been overlooked. Fifth, the onset of glaucoma in bilateral
the HIRA database consists of medical claims data, and cataract cases may have been determined to be earlier than
therefore the information on some of possible risk factors the actual onset date because we defined the onset of glau-
for post–IC surgery glaucoma, such as visual acuity, intraoc- coma as the earlier date of glaucoma conversion between
ular pressure, gonioscopic appearance, and specific surgical the 2 eyes. Sixth and finally, since the HIRA database is an
procedures (ie, IOL position) are not available. Second, to insurance database, post–IC surgery glaucoma cases mistak-
strictly exclude acquired cataract or juvenile cataract, only enly coded as congenital glaucoma (Q15) might have been
patients diagnosed with IC at <1 year of age were included excluded.
in this study. This criterion may have resulted in exclusion In conclusion, our results suggest that glaucoma devel-
of patients whose (properly earlier) IC diagnosis had been oped in 1 in 7 patients who had undergone IC surgery
delayed until after 1 year of age. Third, we identified cases of over the course of a mean follow-up period of 6.2 years,
post–IC surgery glaucoma on the basis of diagnostic codes and 75% of post–IC surgery glaucoma cases could be di-
as well as information on any antiglaucoma medication pre- agnosed within 7.4 years of surveillance. Patients in the
scriptions and ocular surgery history; therefore, we could aphakic state after surgery should be monitored with par-
not include patients who had not been screened for glau- ticular care for development of secondary glaucoma. These
coma, the exclusion of which could have led to an underes- detailed real-world estimates may help promote better un-
timation of the incidence rate of post–IC surgery glaucoma. derstanding of disease pathophysiology and inform health
In another aspect, since optic nerve evaluation is limited by care system planning.

138 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2023

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Funding/Support: Supported by a research grant from Jeju National University Hospital (Jeju-si, ROK) development fund in 2021 (JNUH-202100360001).
The funding organization had no role in the design or conduct of this research.
Financial Disclosures: The authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for
authorship.
Acknowledgements: Drs Ha and Kim served jointly as corresponding authors. We thank the Medical Research Collaborating Center at Seoul National
University Hospital for helping to establish our statistical analysis plan. Outflow of any data is strictly regulated by national security law. The raw data
used in this study can be extracted by request from any qualified investigator through Korea’s national Health Insurance Review and Assessment system.

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