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ARTICLEOPEN

Risk assessment of retinal vascular occlusion after COVID-19
vaccination
Jing-Xing Li
Chun-Ju Lin

1,2,3, Yu-Hsun Wang4, Henry Bair5,6, Shu-Bai Hsu, Connie Chen9,10, James Cheng-Chung Wei4,11,12,13 ✉ and

7,8

2,5,14 ✉1234567890():,;

Coronavirus disease 2019 (COVID-19) vaccines are associated with several ocular manifestations. Emerging evidence has beenreported; however, the causality between the two is debatable. We aimed to investigate the risk of retinal vascular occlusion after
COVID-19 vaccination. This retrospective cohort study used the TriNetX global network and included individuals vaccinated with
COVID-19 vaccines between January 2020 and December 2022. We excluded individuals with a history of retinal vascular occlusionor those who used any systemic medication that could potentially affect blood coagulation prior to vaccination. To compare the riskof retinal vascular occlusion, we employed multivariable-adjusted Cox proportional hazards models after performing a 1:1
propensity score matching between the vaccinated and unvaccinated cohorts. Individuals with COVID-19 vaccination had a higher
risk of all forms of retinal vascular occlusion in 2 years after vaccination, with an overall hazard ratio of 2.19 (95% conﬁdence interval
2.00–2.39). The cumulative incidence of retinal vascular occlusion was signiﬁcantly higher in the vaccinated cohort compared to theunvaccinated cohort, 2 years and 12 weeks after vaccination. The risk of retinal vascular occlusion signiﬁcantly increased during theﬁrst 2 weeks after vaccination and persisted for 12 weeks. Additionally, individuals with ﬁrst and second dose of BNT162b2 andmRNA-1273 had signiﬁcantly increased risk of retinal vascular occlusion 2 years following vaccination, while no disparity was
detected between brand and dose of vaccines. This large multicenter study strengthens the ﬁndings of previous cases. Retinal
vascular occlusion may not be a coincidental ﬁnding after COVID-19 vaccination.
npj Vaccines (2023)8:64 ; https://doi.org/10.1038/s41541-023-00661-7

INTRODUCTION
The extremely contagious severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus
disease 2019 (COVID-19). Since the end of 2020, many vaccines
have been developed, including messenger RNA (mRNA) vaccines(BNT162b2 [Pﬁzer-BioNTech] and mRNA-1273 [Moderna]), adjuvanted recombinant protein vaccines (Novavax), and adenoviral
vector vaccines (ChAdOx1-S vaccine [Oxford/AstraZeneca] andAd26.COV2.S [Janssen-Johnson&Johnson]). Consequently, several
possible complications have been documented due to theincreased vaccination rates.
Retinal vein occlusion (RVO) is the second most prevalent causeof visual loss related to retinal vascular diseases, after diabetic
retinopathy. RVO is related to thromboembolism caused by vessel
compression, vasospasm, or degeneration of vascular walls1.
Retinal artery occlusion (RAO) is caused by vasospasm, vasculitis,
reduced arterial perfusion, and thromboembolism of the retinal
arteries originating from the ipsilateral carotid artery, aortic arch,or heart chambers. Based on the location of the occlusion, RAO
and RVO can be further classiﬁed into central and branch forms.
SARS-CoV-2 infection can precipitate retinal vascular events2,3.
RVO following COVID-19 vaccination is uncommon. However,there is growing literature including case reports on retinal
vascular occlusion following vaccination4–13. Intriguingly, some1studies on retinal vascular occlusion have been related to mRNA
COVID-19 vaccination14,15; the vaccines implicated include mRNA
vaccines, mRNA-127310 and BNT162b27,11,16, as well as the viral
vector-based vaccine ChAdOx16,12,17. However, the quality ofthese data was insufﬁcient to establish a causal relationshipbetween retinal vascular occlusion and COVID-19 vaccination.
This study aimed to determine whether COVID-19 vaccines are
related to an increased risk of retinal vascular occlusion and toraise awareness about the probability of retinal vascular events
due to an increased thrombotic inﬂammatory state associatedwith COVID-19 vaccinations.

RESULTS
Patient characteristics and stratiﬁed analysis
The TriNetX network collected information on a total of 95,156,967
individuals, of whom 7,318,437 met the inclusion criteria. Figure 1
presents the ﬂowchart of patient selection. After excluding caseswith conﬁrmation of COVID-19 diagnosis, 6,755,737 individuals
were separated into two cohorts: 883,177 vaccinated and5,871,737 unvaccinated individuals. In both cohorts, any diagnosisof retinal vascular occlusion six months prior to the index date was
excluded. We also considered the effect of systemic medications
and excluded cases with the use of any antiplatelets,

Department of General Medicine, China Medical University Hospital, Taichung, Taiwan. 2School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan. 4Department of Medical Research, Chung Shan Medical
University Hospital, Taichung, Taiwan. 5Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan. 6Byers Eye Institute, Stanford University School of
Medicine, Stanford, CA, USA. 7College of Medicine, China Medical University, Taichung, Taiwan. 8Department of Nursing, China Medical University Hospital, Taichung, Taiwan.
9
Department of Optometry, Chung Shan Medical University, Taichung, Taiwan. 10Institute of Optometry, Chung Shan Medical University, Taichung, Taiwan. 11Institute ofMedicine, Chung Shan Medical University, Taichung, Taiwan. 12Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan.
13
Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. 14Department of Optometry, Asia University, Taichung, Taiwan. ✉email: jccwei@gmail.com;
doctoraga@gmail.com
3

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2

Fig. 1 The ﬂowchart of study design to identify vaccinated and unvaccinated cohorts. Access date to the TriNetX database was Feburary
15, 2023.

anticoagulants, diuretics, contraceptives, or antihemorrhages
4 weeks prior to the index date. Ultimately, 745,041 vaccinatedand 3,874,458 unvaccinated individuals remained. We matched
739,066 vaccinated cohorts to the unvaccinated cohort at a ratioof 1:1. Table 1 presents the baseline characteristics of the study
population. After matching, the average age of the vaccinatedgroup was 52.5 ± 18.5 years, whereas the unvaccinated group was
52.2 ± 18.2 years. There were no differences in any of the variables
between the two cohorts. Table 2 reveals the stratiﬁed analysis
based on age, sex, and race. Individuals aged from 18 to 64 years
has increased risk of retinal vascular occlusion except for CRAO.
Brand of vaccines
In the subgroup analysis, the ﬁrst dose was deﬁned as individuals
receiving a single dose of the COVID-19 vaccine, and the second
dose was deﬁned as individuals receiving a second dose that was
identical to the ﬁrst dose. Table 3 presents the results ofvaccination with various brands of COVID-19 vaccines. The risk
npj Vaccines (2023) 64

of retinal vascular occlusion increased signiﬁcantly after the ﬁrst
and second doses of BNT162b2 or mRNA-1273 in a 2-year period.
The risks were not different between BNT162b2 and mRNA-1273
recipients. Though the risk of retinal vascular occlusion waselevated following the ﬁrst dose of Ad26.COV2.S, the risk was not
signiﬁcant. Twelve weeks after vaccination of all brands ofvaccines, the risk of retinal vascular occlusion increased nonsigniﬁcantly.
Risk of retinal vascular occlusion at 2 years and 12 weeks
Figure 2 presents the risk of retinal vascular occlusion at 2 years
and 12 weeks after the uptake of COVID-19 vaccines. Supplementary Table 1 shows the original data with number of events andincidence rate. The overall risk of retinal vascular occlusion in thevaccinated cohort was 2.19 times higher than that in theunvaccinated cohort at 2 years (95% Cl 2.00–2.39). Two years
after vaccination, the chances of all subtypes (BRAO, BRVO, CRAO
and BRVO) of retinal vascular occlusion increased signiﬁcantly in
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Table 1.

Demographic characteristics of patients with and without COVID-19 vaccination.
Before PSM

After PSM

VaccinatedN = 745,041

UnvaccinatedN = 3,874,458

SMD

VaccinatedN = 739,066

UnvaccinatedN = 739,066

SMD

52.6 ± 18.5

46.7 ± 18.1

0.322

52.5 ± 18.5

52.2 ± 18.2

0.016

Female441083 (59.2)

2092041 (54.0)

0.105436871 (59.1)

434259 (58.8)

0.007

Male
Unknown

303757 (40.8)
201 (0.027)

1619285 (41.8)
163132 (4.210)

0.021

301994 (40.9)
201 (0.027)

269103 (36.4)
35704 (4.831)

0.091

White

549172 (73.7)

2437160 (62.9)

0.234

543886 (73.6)

550999 (74.6)

0.022

African American

89896 (12.1)

635883 (16.4)

0.12589699 (12.1)

91490 (12.4)

0.007

Asian

26491 (3.6)

84507 (2.2)

0.082

26065 (3.5)

25707 (3.5)

0.003

Hypertensive diseases

249533 (33.5)

508399 (13.1)

0.496243707 (33.0)

246040 (33.3)

0.007

Type 2 diabetes mellitus
Hyperlipidemia

112966 (15.2)
222993 (29.9)

211428 (5.5)
398604 (10.3)

0.323
0.505

108896 (14.7)217306 (29.4)

105099 (14.2)
220485 (29.8)

0.015
0.009

Ischemic heart diseases

73108 (9.8)

122073 (3.2)

0.27369808 (9.4)

65150 (8.8)

0.022

Cerebrovascular diseases

41250 (5.5)

67952 (1.8)

0.20338795 (5.2)

34472 (4.7)

0.027

Glaucoma23249 (3.1)

35391 (0.9)

0.15722601 (3.1)

14889 (2.0)

0.066

Arterial thromboembolism

6755 (0.9)

7517 (0.2)

0.0966140 (0.8)

3957 (0.5)

0.036

Venous thromboembolism

16777 (2.3)

24679 (0.6)

0.13615321 (2.1)

12842 (1.7)

0.025

Pregnancy

19101 (2.6)

85791 (2.2)

0.023

19065 (2.6)

17731 (2.4)

0.012

Overweight and obesity
Smoking

110743 (14.9)
64609 (8.7)

217725 (5.6)
172295 (4.4)

0.309
0.171

106495 (14.4)
62553 (8.5)

104769 (14.2)
60899 (8.2)

0.007
0.008

ACEI/ARB

136336 (18.3)

283478 (7.3)

0.333132620 (17.9)

134004 (18.1)

0.005

Beta-blocker

122425 (16.4)

243745 (6.3)

0.324

118402 (16.0)

116162 (15.7)

0.008

CCB

86635 (11.6)

180981 (4.7)

0.25684307 (11.4)

80676 (10.9)

0.016

Metformin55369 (7.4)

112287 (2.9)

0.20653520 (7.2)

53063 (7.2)

0.002

Age
Sex

Race

Comorbidities

Medications

Lipid lowering agents

164276 (22.0)

329242 (8.5)

0.384

159650 (21.6)

160913 (21.8)

0.004

Corticosteroids
NSAIDs163232 (21.9)
191038 (25.6)333649 (8.6)
507084 (13.1)

0.376
0.322

157965 (21.4)
186271 (25.2)

158061 (21.4)
188800 (25.5)<0.001
0.008

Antipsychotics

61980 (8.3)

137901 (3.6)

0.202

59578 (8.1)

57996 (7.8)

0.008Previous hospitalization

106573 (14.3)

224481 (5.8)

0.286102014 (13.8)

97498 (13.2)

0.018

ACEI angiotensin converting enzyme inhibitor, ARB Angiotensin II receptor blockers, CCB Calcium-channel blockers, N number, NSAIDs non-steroidal antiinﬂammatory drugs, PSM propensity score matching, SMD standardized mean difference.

the vaccinated cohort. The hazards of retinal vascular occlusion
and its subtypes were higher within 12 weeks than those at 2
years. Considering the potential acute consequences of COVID-19
vaccinations and its temporary effect, we investigated the biweekly incidence of the four forms of retinal vascular occlusion
within 12 weeks of COVID-19 vaccination.

occlusion and its subtypes were signiﬁcantly increase in vaccinated than in the unvaccinated cohorts two years after vaccination (log-rank p < 0.001). This trend was also observed within 12
weeks after COVID-19 vaccination (log-rank p < 0.001) (Supplementary Fig. 1).

Bi-weekly risk of retinal vascular occlusion in 12 weeks
Figure 3 presents the results of the subgroup analysis of bi-weekly
risks of retinal vascular occlusion. Supplementary Table 2 provides
the original data with number of events and incidence rate. Cox
multivariate analysis showed that the risk of retinal vascularocclusion in the vaccinated group was higher than that in theunvaccinated group at within 2 weeks of vaccination, which
persisted for 12 weeks. This effect affected all subtypes except
CRAO at 10–12 weeks after vaccination.
Figure 4 demonstrated the results of Kaplan–Meier analysis,
which revealed that the cumulative incidence of retinal vascularTime course of risk of retinal vascular occlusion
Figure 5 depicts the time evolution of risks associated with retinal
vascular occlusion and its subtypes. The risk of retinal vascularocclusion increased 27 days following vaccination against COVID-19.
The risk of branch retinal vascular occlusion was greater at 6 and3 days for BRAO and BRVO, respectively. In contrast, theprobability of central retinal vascular occlusion was greater at 15
and 45 days for CRAO and CRVO. Supplementary Table 3
enumerates hazards of retinal vascular occlusion and its subtypes
in 3-day interval after vaccination.

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npj Vaccines (2023) 64

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Table 2.

Stratiﬁed analysis of risk of retinal vascualr occlusion exposed
to COVID-19 vaccines compared with unvaccinated individuals in 2
years.
Number of events

Age 18–64
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
Age ≥ 65
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
FemaleRetinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
Male
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
White
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
African American
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO
Asian
Retinal vascular occlusionb
BRAO
BRVO
CRAO
CRVO

VaccinatedUnvaccinated506,701
415
95
174
45
156
236,804
1108
251
443
136
390
437,682
782
168
332
99
272
302,269
731
178
277
87
266
545,223
1146
278
465
135
396
89,833
218
40
84
37
83
26,080
40
<10a
22
<10a
<10a

506,701
240
63
86
34
78
236,804
520
140
180
89
169
437,682
359
92
133
58
115
302,269
328
92
104
55
104
545,223
546
149
179
86
175
89,833
118
25
42
19
41
26,080
16
<10a
<10a
<10a
<10a

HR and 95% Cl

1.87 (1.58–2.19)
1.65 (1.19–2.28)
2.21 (1.69–2.87)
1.47 (0.93–2.31)
2.19 (1.65–2.88)
2.37 (2.12–2.62)
2.07 (1.67–2.54)
2.70 (2.26–3.21)
1.74 (1.32–2.28)
2.55 (2.12–3.05)
2.33 (2.05–2.64)
2.02 (1.56–2.61)
2.64 (2.15–3.23)
1.88 (1.34–2.60)
2.54 (2.04–3.16)
2.40 (2.10–2.73)
2.17 (1.67–2.80)
2.81 (2.23–3.52)
1.69 (1.20–2.37)
2.79 (2.21–3.50)
2.31 (2.08–2.55)
2.12 (1.72–2.59)
2.79 (2.34–3.31)
1.78 (1.35–2.34)
2.52 (2.10–3.01)
2.05 (1.63–2.56)
1.85 (1.11–3.07)
2.18 (1.50–3.16)
2.14 (1.22–3.73)
2.28 (1.56–3.31)
2.62 (1.46–4.68)
1.93 (0.46–8.11)
2.84 (1.25–6.39)
3.69 (0.41–33.00)
1.78 (0.64–4.93)a

Due to policy of TriNetX, any number less than 10 will be automaticallyassigned as <10.
b
The diagnosis of retinal vascular occlusion was determined by its
diagnostic codes, rather than by the sum of its subtypes.
HR Hazard ratio, 95% CI 95% conﬁdence interval.

DISCUSSION
We demonstrated a higher risk and incidence rate of retinal
vascular occlusion following COVID-19 vaccination, after adjustingfor potential confounding factors18. The risk of retinal vascularocclusion, except for CRAO, has been promptly observed inindividuals receiving vaccines against SARS-CoV-2. The risk factors
npj Vaccines (2023) 64

for retinal vascular occlusion include diabetes, hypertension,
obesity, coronary artery disease, and stroke19–21. To ensure thereliability of the results, we appropriately balanced the baselinecharacteristics in both cohorts before analysis.
The widespread occurrence of microvascular thrombosis in
COVID-19 patients have been demonstrated22. Vaccination with
ChAdOx1 nCoV-19 can result in the rare development of immune
thrombotic thrombocytopenia mediated by platelet-activating
antibodies against platelet factor 4 (PF4), which clinically mimics
autoimmune heparin-induced thrombocytopenia23. A large cohort
study24 showed that the risk of VTE slightly increased 1.10-fold
8–14 days after ChAdOx1 nCoV-19 vaccination but found nodifference for individuals who were administered BNT162b2
vaccination; the risk of ATE following ChAdOx1 nCoV-19 and
BNT162b2 vaccination increased 1.21-fold and 1.06-fold,respectively.
Thrombosis that manifests before thrombocytopenia is referred
to as vaccine-induced immune thrombotic thrombocytopenia(VITT). Two adenoviral vector-based immunizations, ChAdOx1
nCoV-19 and Ad26.COV2.S, have been associated with thedevelopment of VITT. VITT cerebral venous sinus thrombosis ispredominantly from adenovirus viral vector vaccines. The
pathological mechanism of thrombosis has been hypothesized
to entail either an innate or adaptive response, involving theactivation of B and T cells and CD4 T cells are essential for
regulating the production of PF4/heparin-speciﬁc antibodies25.
VITT is a very rare, life-threatening adverse complication with a
23% overall mortality rate26. Certain inﬂammatory vaccine
adjuvants and delivery techniques may induce immune cell
recruitment during the VITT. Antibodies that detect platelet-boundPF4 are the cause of VITT. These antibodies are immunoglobulin G(IgG) molecules that activate platelets by binding to platelet FcγIIawith a modest afﬁnity27. VITT typically appears as uncommon
thromboses (cerebral venous sinus thrombosis and splanchnicvein thrombosis), although it can also manifest as typicalthromboses (stroke, pulmonary embolism, and deep vein thrombosis) with severe thrombocytopenia.
Thrombosis with thrombocytopenia syndrome (TTS) is a moregeneral descriptive name for the syndrome of thrombosis andthrombocytopenia of any cause following COVID-19 vaccination.
Some individuals with TTS may not have been evaluated for antiPF4 antibodies; or have causes of thrombosis and thrombocytopenia other than VITT, such as antiphospholipid syndrome, cancerassociated thrombosis and thrombocytopenia, thrombotic thrombocytopenic purpura, or disseminated intravascular coagulation.
A series of 65 individuals with serologically conﬁrmed VITT who
repeated functional assays over time found that the functional
assays became negative in 74% of individuals, at a median of
15.5 weeks (95% Cl, 5–28 weeks)28. VITT plays a fundamental role
in retinal vascular disease and may well explain the signiﬁcantly
increased risk of all forms of retinal vascular occlusion in 12 weeks
observed in the subgroup analysis. In an examination of thetemporal change of the risk of retinal vascular occlusion, which
increased signiﬁcantly shortly after vaccination, especially BRAO
and BRVO. The highest hazards of subtypes of retinal vascularocclusion varied. The riskiest period after COVID vaccination for
BRAO, BRVO, CRAO, and CRVO was 6, 3, 15, and 45 days,
respectively. For BRAO and BRVO, direct embolism may be thepreferred mechanism, whereas for CRAO and CRVO, VITT
secondary to immunization may be the cause. VITT has a
predilection for venous thrombosis in the CNS, splanchnic or
adrenal veins, with patients presenting neurologic signs inaddition to fever and mild bruising as early as 4–28 and up to
30 days post-COVID-19 vaccination. The relevant literatures on it
are extremely limited29.
The Netherlands’ Lareb30 showed that the incidence rate of VITT
and TTS in individuals receiving the ChAdOx1-S vaccine was 7.7
per million vaccinations. Among them, 13.4 per million people
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J.-X. Li et al.

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Table 3.

The risk of reintal vascular occlusion signiﬁcantly increased in individuals receiving the ﬁrst and second doses of BNT162b2 and mRNA1273 within 2 years.
VaccinatedNumber of events

Unvaccinated
Incidence (%)

Number of events

0.036

92

Incidence (%)

HR (95% CI)

0.021

1.48 (1.12–1.94)

0.030

1.36 (1.04–1.77)

2 years
BNT162b2
First dose

111,491
120

Second dose

111,491

96,135
116

96,1350.042

107mRNA-1273
First dose

50,3820.064

79
47,5360.044

1.48 (1.10–1.97)

Second dose

114
47,53650,382

106

0.069

75

0.048

1.50 (1.11–2.02)

0.140

<10*

0.140

2.35 (0.74–7.39)

-

NA

0.083

1.65 (0.98–2.75)

0.111

1.36 (0.84–2.18)

Ad26.COV2.S#First dose

7158
<10*

Second dose

7158

162
0

162
-

0

0.108

23

12 weeks
BNT162b2
First dose

111,491
40

Second dose

111,491

96,13540

96,1350.121

29mRNA-1273
First dose

50,3820.226

2247,5360.157

1.35 (0.78–2.31)

Second dose32
47,53650,382

33

0.223

23

0.158

1.37 (0.80–2.33)

0.140

<10*

0.140

3.98 (0.44–35.60)-

NAAd26.COV2.S#First dose

7158
<10*

Second dose

7158

162
0

162
-

0

HR Hazard ratio, NA not applicable, 95% CI 95% conﬁdence interval.
*Due to policy of TriNetX, any number less than 10 will be automatically assigned as <10.
#
A single dose of Ad26.COV2.S was required according to its package insert.

who received the ﬁrst dose and 1.7 per million people who
received the second dose. The reported rates of retinal vascularocclusion for Ad26.COV2.S, BNT162b2, and mRNA-1273 per million
vaccines were 5.7, 0.05, and 0.2, respectively. The Netherlands
Pharmacovigilance Centre Lareb has received three reports of
VITT/TTS with BNT162b2 and mRNA-1273; however, the associations are not sufﬁciently strong. A large international network
cohort study31 demonstrated a 30% greater risk of thrombocytopenia after a single dose of the ChAdOx1-S vaccine, as well as atrend toward an increased risk of venous TTS after vaccination of
Ad26.COV2.S compared with BNT162b2. In this study, thoughhigher risk of retinal vascular occlusion on Ad26.COV2.S recipientswas observed in 2-year and 12-week periods, there is no
signiﬁcant increase. Intriguingly, a trend was noted that the risk
is more pronounced following immunization with Ad26.COV2.S
than BNT162b2 or mRNA-1273.
The SARS-CoV-2 genome encodes ten genes, two-thirds ofwhich are nonstructural. The other one-third of the genome
Published in partnership with the Sealy Institute for Vaccine Sciencescomprises four major structural genes, including spike, envelope,matrix, and nucleocapsid proteins, as well as ﬁve auxiliary
proteins32. Messenger RNA vaccines contain fully functionalmRNAs that can be directly translated into the S protein33,34.
BNT162b2 and mRNA-1273, two mRNA vaccines currently in broaduse, are technologically extremely similar. They comprise codonoptimized sequences for effective production of the whole S
protein and utilize the actual signal sequence for its biosynthesis.
Molecular mimicry of the S protein, which shares sequencehomology with human proteins, may play a central role in retinal
vascular occlusion35.
The global prevalence of RVO, BRVO, and CRVO in individuals
aged 30–89 years was 0.77%, 0.64%, and 0.13%36. In the UnitedStates, the prevalence of RVO, BRVO, and CRVO is 0.7%–0.8%,
0.6%, and 0.1%–0.2%, respectively37,38. However, studies on theprevalence of RAO are limited. The current study revealed a strong
correlation between vaccination with a mRNA vaccine and retinal
vascular occlusion. However, we recommend that individuals
npj Vaccines (2023) 64

J.-X. Li et al.

6
without a history of severe allergic reaction to any component of
the vaccine be vaccinated to protect against COVID-19, owing to
the lack of deﬁnite causation between retinal vascular occlusion

Fig. 2 Forest plot of risk of retinal vascular occlusion with 2-year
and 12-week follow-up. A 2-year, and (B) 12-week. HR hazard ratio,
LCL lower conﬁdence limit, UCL upper conﬁdence limit, US UnitedStates.

and vaccinations. Based on the ofﬁcial COVID-19 death reports, it
is estimated that vaccinations have prevented 14.4 million excess
COVID-19 deaths worldwide between December 2020 and
December 202139. Thus, vaccination is the most effective method
for preventing the spread of SARS-CoV-2.
The number of reported ophthalmic complications hasremained low, and vaccine-related retinal vascular occlusion isvery rare, although the number of COVID-19 vaccinations isenormous. As of August 2 2022, 223.04 million people hadcompleted a primary series of COVID-19 vaccines in the US39.
However, we still suggest that patients on medications that mayalter blood osmolarity should be aware of this possibility ofadverse effects. Additional research is required to draw a solid
conclusion regarding the association between retinal vascularocclusion and COVID-19 vaccines.
Strengths and weakness
Emerging cases of retinal vascular occlusion in outpatient settings
have prompted us to address this concern. However, since this is
the ﬁrst study on this topic, these discoveries may have asigniﬁcant impact on public health. To ensure the validity of theanalysis, we conducted a comprehensive evaluation of confounding factors. However, this study had several limitations. First, since
the existence of retinal vascular occlusion was deﬁned bydiagnostic codes, the diagnostic accuracy cannot be further

Fig. 3 Bi-weekly average hazard ratio of retinal vascular occlusion and its subtypes estimated by cause-speciﬁc Cox proportional hazard
regression model after COVID-19 vaccination. A retinal vascular occlusion, (B) branch retinal artery occlusion, (C) branch retinal vein
occlusion, (D) central retinal artery occlusion, and (E) central retinal vein occlusion. HR hazard ratio, LCL lower conﬁdence limit, UCL upper
conﬁdence limit.
npj Vaccines (2023) 64

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Fig. 4 Kaplan–Meier curves showing cumulative incidence of retinal vascular occlusion and its subtypes in 2 years. A retinal vascularocclusion, (B) branch retinal artery occlusion, (C) branch retinal vein occlusion, (D) central retinal artery occlusion, and (E) central retinal vein
occlusion.

conﬁrmed. Second, the HR can be calculated using the TriNetX
database; however, the p-value is not provided. Third, despite thefact that multiple confounding variables were accounted for,residual confounding variables may still exist and bias the results.
Additional clinical investigations are required to validate the
efﬁcacy of mRNA vaccination against retinal vascular occlusion.
Fourth, underprivileged people are more difﬁcult to seek medical
help under COVID-19 pandemic thought they do not have to pay
for COVID-19 vaccines. Moreover, retinal vascular occlusion withno or mild symptoms may not be noted. Thus, under-reporting of
retinal vascular occlusion and vaccination may bias the study tosome extent. Lastly, TriNetX collects patient information only
when the patient receives care from one of the participating
healthcare organizations. The inclusion of care obtained from
Published in partnership with the Sealy Institute for Vaccine Sciences

other institutions was not possible in this analysis. Loss to followup has the potential to distort the distributions of covariates andoccurrence of outcomes. In brief, the data should be evaluatedcritically and cautiously owing to the retrospective nature of thisinvestigation.
This large-scale cohort spanning two years investigate theassociation between retinal vascular occlusion and COVID-19
vaccination. A 2.19-fold increased risk of retinal vascular occlusion
after COVID-19 vaccination was observed. Limited evidence andlow frequency of the disease has complicated the establishmentof a deﬁnitive association between both. The current ﬁndings
support the conclusions of this case series. This emphasizes thenecessity for a thorough study and ophthalmologists to consider
the likelihood of retinal vascular occlusion in vulnerable patients
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Fig. 5 The risks of retinal vascular occlusion and its subtypes signiﬁcantly elevated following COVID-19 vaccination. Time course ofhazard ratios of retinal vascular occlusion and its subtypes following COVID-19 vaccination was demonstrated. Of note, the risk of branchretinal vascular occlusion was extremely high after vaccination.

following the administration of COVID-19 vaccines. Vaccination issuggested to protect against COVID-19, since the incidence ofretinal vascular occlusion remains extremely low.
METHODS
Study design and participantsThis retrospective cohort study was based on data provided by
the TriNetX global network, a large and federated research
network; numerous renowned studies have employed thisdatabase40–44. Data for this analysis were restricted to patient
data from the United States collected between January 1, 2020and December 31, 2022, derived from 52 health care organizations. The TriNetX federated network received a waiver from theWestern institutional review board since it only aggregated counts
and statistical summaries of de-identiﬁed information; however,protected health information was not collected, and no studyspeciﬁc activities were performed in retrospective analyses. The
study protocol was approved by institutional review board of
Chung Shang Medical University Hospital.
Outcomes and covariates
The International Classiﬁcation of Diseases, Tenth Revision, ClinicalModiﬁcation (ICD-10-CM) codes H34.1 and H34.2, respectively,
deﬁne central retinal artery occlusion (CRAO) and branch retinal
artery occlusion (BRAO). The ICD-10-CM codes H34.81 and H34.83
deﬁne central retinal vein occlusion (CRVO) and branch retinal
vein occlusion (BRVO), respectively. ICD-10-CM code H34 indicatedretinal vascular occlusion. Participants with COVID-19 infection
identiﬁed by a positive polymerase chain reaction or immunoassay result for immunoglobulin A, G, or M in the plasma or serum
were excluded. Participants who received mNRA vaccines
npj Vaccines (2023) 64

BNT162b2 or mRNA-1273 which were documented in electronic
medical records during the study period were included. The
control group consisted of individuals who had not received any
vaccinations. Only individuals with a ﬁrst-time diagnosis of retinal
vascular occlusion during the study period were included in boththe case and control groups.
Patients were excluded if a diagnosis of retinal vascular occlusion
was made six months before the index date (the earliest date of
COVID-19 vaccination) or if they had received antithrombotics,
diuretics, oral contraceptives, or antihemorrhagics four weeks prior
to the index date. Antithrombotic agents include antiplatelet
agents (aspirin, receptor P2Y12 antagonists, and glycoprotein IIb/IIIa[GPIIb/IIIa] inhibitors), anticoagulant (heparin, warfarin, direct oral
anticoagulants, and direct thrombin inhibitors), and ﬁbrinolytics(plasminogen activator inhibitors). COVID-19 was identiﬁed using
TriNetX-provided criteria and ICD-10-CM codes in accordance with
the Centers for Disease Control and Prevention coding guidelines.
Supplementary Table 4 listed codes of laboratory, diagnosis, andmedications adopted on TriNetX platform, as well as ICD-10-CM
codes of comorbidities and Anatomical Therapeutic Chemical
codes of common-used medications.
Statistical analysis
We used 1:1 propensity score matching of age, sex, race,
comorbidities, medications and previous hospitalization to reduce
selection bias and to optimize the variates of the case and control
cohorts. The closest propensity scores for the cases and controls
were estimated. We used the nearest-neighbor algorithm toderive matched pairs, with values of standardized mean difference<0.1, to indicate a signiﬁcant difference between the cases andcontrols. Crude and multivariable-adjusted Cox proportional
hazards models were used to compare the risk of outcomes
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9
between the cases and controls. The results of the comparisonsare presented as HRs and 95% conﬁdence intervals (CIs).
Chi-square (χ2) tests were performed to analyze the homogeneity of category variables, including age, sex, race, andcomorbidities, between the vaccinated and unvaccinated groups.
Comorbidities included hypertensive diseases (ICD-10-CM codes
I10–I16), overweight and obesity (ICD-10-CM code E66), type 2
diabetes mellitus (ICD-10-CM code E11), dyslipidemia (ICD-10-CM
code E78), cerebrovascular diseases (ICD-10-CM codes I60–I69),
ischemic heart diseases (ICD-10-CM code I82), glaucoma (ICD-10CM code H40), arterial thromboembolism (ATE) (ICD-10-CM codeI74), and venous thromboembolism (VTE) (ICD-10-CM code I82).
The incidence rates of the retinal vascular occlusion subtypes were
calculated for both groups. The 95% conﬁdence interval (CIs) for
the risk of retinal vascular occlusion was calculated. The
Kaplan–Meier survival curve was plotted to describe thecumulative incidence of retinal vascular occlusion between
the two groups, and the differences between the two groups
were evaluated using the log-rank test. Statistical signiﬁcance wasset at p < 0.05. TriNetX obscures counts in studies with counts lessthan 10 to protect patient health information by rounding it to thenearest 10. Whenever such rounding occurred in the analysis
conducted in this study, it was identiﬁed and reported.
Reporting summary
Further information on research design is available in the Nature
Research Reporting Summary linked to this article.
DATA AVAILABILITY
Data is available from the TriNetX global network. Requests for data can be sent as
logging on TriNetX platform (https://live.trinetx.com/).

CODE AVAILABILITY
Data is available from the TriNetX global network. Requests for data can be sent as
logging on TriNetX platform (https://live.trinetx.com/).

Received: 8 November 2022; Accepted: 11 April 2023;

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AUTHOR CONTRIBUTIONS
J.-X.L. and Y.-H.W. had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. Acquisition andanalysis of data, statistical analysis: Y.-H.W. Interpretation of data, concept and design,and drafting of the manuscript: J.-X.L. Critical revision of the manuscript for important
intellectual content: J.-X.L, S.-B.S., H.B., C.-J.L, C.C. Supervision: J.C-C.W., C.-J.L. Y.-H.W. is
the co-ﬁrst author.

ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41541-023-00661-7.
Correspondence and requests for materials should be addressed to James ChengChung Wei or Chun-Ju Lin.
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COMPETING INTERESTS
The authors declare no competing interests.

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