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Ocular Immunology and Inflammation
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ioii20
Prenatal and Postnatal Ocular Abnormalities
Following Congenital Zika Virus Infections: A
Systematic Review
Anis Mahmoud, Léo Pomar, Veronique Lambert, Olivier Picone & Najeh
Hcini
To cite this article: Anis Mahmoud, Léo Pomar, Veronique Lambert, Olivier Picone & Najeh
Hcini (13 Feb 2024): Prenatal and Postnatal Ocular Abnormalities Following Congenital
Zika Virus Infections: A Systematic Review, Ocular Immunology and Inflammation, DOI:
10.1080/09273948.2024.2314086
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REVIEW ARTICLE
Prenatal and Postnatal Ocular Abnormalities Following Congenital Zika Virus
Infections: A Systematic Review
Anis Mahmoud, MD, PhD
a,b
, Léo Pomar, PhD
c,d
, Veronique Lambert, MD
e
, Olivier Picone, MD, PhD
f
,
and Najeh Hcini, MD, MSc
e,g
a
Department of Ophthalmology, Tahar Sfar University Hospital, Mahdia, Tunisia;
b
Faculty of Medicine, University of Monastir, Monastir, Tunisia;
c
Ultrasoundand Fetal Medicine, Department “Woman-Mother-Child”, Lausanne University Hospital and University of Lausanne, Lausanne,
Switzerland;
d
School of Health Sciences (HESAV), University of Applied Sciences and Arts Western Switzerland, Lausanne, Switzerland;
e
Department
of Obstetrics and Gynaecology, West French Guiana Hospital Center, Saint-Laurent-du-Maroni, French Guiana;
f
Service Gynécologie Obstétrique,
Hôpital LouisMourier, Hôpitaux Universitaires Paris Nord Val de Seine, Assistance Publique : Hôpitaux de Paris, Université Paris Diderot, Colombes,
France;
g
INSERM CIC1424 Centre d’Investigation Clinique Antilles Guyane, Cayenne, French Guiana
ABSTRACT
Objective: To assess fetal and neonatal eyes abnormalities and their progression during the last ZIKV
outbreak and summarize learned lessons.
Methods: A systematic review and meta-analysis was conducted by a team of obstetricians and
ophthalmologists.
Results: Studies reporting ocular abnormalities during the prenatal (n = 5) and postnatal (n = 24) periods
were included in the analysis. In the prenatal period, the most common ocular ndings were intraocular
calcication cases (4/6, 66.6%) and microphthalmia (3/6, 50%). Postnatal ocular abnormalities of con-
genital ZIKV infection were described after birth in 479 cases. Among them microphthalmia was reported
in 13 cases (13/479, 2.7%). Posterior segment (retina and optic nerve) was the most aected structure,
consisting of pigmentary changes (229/479, 47.8%), macular chorioretinal atrophy (216/479, 45%), optic
nerve atrophy (181/479, 37.8%), increased cup-to-disk ratio (190/479, 39.6.%), optic nerve hypoplasia (93/
479,19.4%), vascular changes (26/479, 5.4%), and retinal coloboma (20/479, 4.1%). The anterior segment
was involved in 4.6% (22/479) of cases, including cataract (9/479, 1.8%), lens subluxation (1/479, 0.2%), iris
coloboma (5/479, 1%), and congenital glaucoma (7/479, 1.4%). These ocular anomalies were isolated in
one case (1/479, 0.2%) and multiple anomalies were found in the other cases. Long-term visual disorders
have been described, with no possible improvement and even a worsening of some of the ocular
anomalies previously observed. No reactivation of ocular lesions was observed.
Conclusion: This review highlights the severe ocular abnormalities associated with congenital ZIKV
infections. The importance of multidisciplinary communication between the obstetrician, the maternal-
fetal medicine specialist, and the ophthalmologist is emphasized.
Protocol registration: This systematic review was registered with the International Prospective Register
of Systematic Reviews (PROSPERO), registration440 188.
ARTICLE HISTORY
Received 26 July 2023
Revised 6 December 2023
Accepted 30 January 2024
KEYWORDS
Congenital Zika syndrome;
eyes; microcephaly;
pregnancy; Zika virus
Congenital infection by the Zika virus has caused great concern
throughout the world and was declared a global health emergency
by the World Health Organization.
1
While infections are often
asymptomatic or pauci-symptomatic in the healthy adult popula-
tion, ZIKV is more of a threat to the developing fetus. Links
between congenital ZIKV infections and birth defects, long-
term neurodevelopment, and neurosensory alterations are now
well documented.
2,3
Eye and hearing abnormalities were reported
in many cohorts of infected children.
3,4
Ocular manifestations of
ZIKV arise from the ability of the virus to cross both the placental
and blood-brain barriers. In ocular examinations, anterior and
posterior segments were involved with a large spectrum of
lesions.
5,6
Limited resources in many of the low-income countries
affected by the epidemic have negatively affected the diagnosis of
these ocular anomalies leading to an underestimation of the
neurosensory impact of the Zika virus. The 2015–17 pandemic
highlighted that pregnant women and fetuses are particularly
vulnerable to emergent infections such as arboviruses.
Neurotropism of ZIKV, but also other arboviruses such us
Tonate virus
7
and West Nile virus,
8
can result in neurodeve-
lopment and neurosensory alterations. This has called atten-
tion to the importance of clarifying the pathophysiological and
clinical features of ocular ZIKV-induced abnormalities.
Ultrasonographic ocular lesions are rarely described as
a gateway to fetal infection. Rare observations of ophthalmo-
logic lesions due to ZIKV have been reported during the
prenatal period. Given the current global context with the
emergence of multiple infectious agents and climate change,
this topic requires heightened awareness. A multidisciplinary
approach is necessary to comprehensively evaluate the conse-
quences of such congenital infections. The goal of this work
was to summarize and assess the pre- and post-natal history of
CONTACT Najeh Hcini, MD, MSc hcininajeh@gmail.com Department of Obstetrics and Gynaecology, West French Guiana Hospital Center, 1465 Boulevard de
la Liberté, BP 245, 97393 Saint-Laurent-du-Maroni, French Guiana
OCULAR IMMUNOLOGY AND INFLAMMATION
https://doi.org/10.1080/09273948.2024.2314086
© 2024 Taylor & Francis Group, LLC
ZIKV infection during the most recent outbreak in relation to
ocular abnormalities.
Materials and methods
Search strategy
Searches for prenatal or pediatric reports of ZIKV congenital
infection were performed using PubMed, Web of Science™,
and Embase
®
databases from inception of the study to
December 31, 2022 using the following key words: “Zika
virus” and “pregnancy;” “ocular abnormalities;” “congenital
disease;” and “congenital infection.”
Eligibility criteria and study selection
All original studies (cohort, case-control, case reports, and
series) describing at least one case of eye involvement due to
confirmed congenital Zika virus infection were considered.
For articles describing ocular prenatal findings, the period
extended from 2016 (the first case described prenatally)
9
to
2022. Articles focusing on ocular postnatal abnormalities cov-
ered the period from 2015 (the first article retrieved in the
literature search) to 2022.
10
Reports were limited to those
written in English or French. The exclusion criteria were:
absence of confirmation of ZIKV infection (suspected infec-
tion without biological confirmation or diagnosis concluded
after exclusion of other infections); review articles; and articles
with data duplication.
Data extraction
We reviewed the full text of the selected articles to identify
studies meeting our selection criteria. The results of antenatal
and postnatal cases were recorded.
Assessment of risk bias
In the postnatal group, we considered only fetal and neonatal
abnormalities in living fetuses or neonates to avoid including
false ocular abnormality induced by tissue damage after fetal
death. In addition, we included ocular histopathologic findings
in fetus after medical termination of pregnancy to better docu-
ment ocular anomalies.
Data synthesis
First, we summarized the most common findings from antenatal
ocular ultrasound that should be investigated in possible or con-
firmed congenital ZIKV cases. Next, we described the fetal ocular
lesions encountered in the postnatal period and the ocular optical
coherence tomography (OCT) findings of these lesions. Finally,
we discussed the course of ocular pathology during follow-up.
Results
Study selection
In total, 112 articles were screened for eligibility. Only 46 met
the criteria for full-text assessment, of which 29 met the criteria
for inclusion in our review. 17 articles were excluded because
of a lack of biological documentation of ZIKV infection.
Maternal ZIKV infection was based on molecular tests (i.e.,
reverse transcription polymerase chain reaction (RT-PCR) and
serological tests for IgM immunoglobulin neutralization and
plaque reduction). The flowchart for selection of included
articles is presented in Figure 1. In total, 479 cases of congeni-
tal ZIKV infection were reported in the postnatal period.
Study characteristics
Ocular abnormalities were described antenatally in only 6
cases and postnatally in 479 cases, 119 of which were reas-
sessed during follow-up and included in the “progression of
ocular lesions” group.
Overview of results
Antenatal ocular ultrasonographic findings
Ocular abnormalities were rarely described in the antenatal
period. From 2016 to 2022, only six cases were reported.
2–6
The first case describing ocular abnormality detected at
antenatal ultrasound scan was reported by Oliveira Melo
et al. in 2016
9
at 29 weeks of gestation. It was associated with
fetal microcephaly. The described lesions were bilateral catar-
acts, intraocular calcifications, and unilateral microphthalmia.
Cases with antenatal ultrasonographic ocular abnormalities
and extra ocular associated signs are described in Table 1. The
most common prenatal ocular findings were intraocular calci-
fications (4/6, 66.6%) and microphthalmia (3/6, 50%). Cataract
was found in only one case (1/6, 16.6%). Based on the available
data, ocular involvement was always associated with other
extraocular anomalies. The most frequently reported associa-
tion was central nervous system (CNS) involvement, especially
microcephaly (6/6, 100%), parenchymal calcifications (5/6,
83%), cerebellar hypoplasia (4/6, 66.6%), and ventriculomegaly
(3/6, 50%). An association with arthrogryposis, which reflects
brainstem involvement, has also been reported (1/6, 16.6%).
Gestational age at the time of maternal infection was avail-
able in four cases: two in the first trimester and two in
the second trimester. No cases of antenatal ocular ultrasono-
graphic findings were reported after maternal ZIKV infection
diagnosed during the third trimester of pregnancy. Pregnancy
outcomes were only available in four cases. Among them, two
neonatal deaths (2/4, 50%) and one premature birth (1/4, 25%)
were reported.
9,12–15
In the context of maternal Zika infection during pregnancy,
fetal ocular abnormalities were always associated with neuro-
logic damage.
9,12–15
Severe ocular antenatal anomalies were
most often associated with maternal infections in the first
and second trimesters.
Postnatal ocular ndings
Ocular abnormalities in congenital ZIKV infection were
described after birth in 24 articles that examined 1291
cases.
16–39
Among them, only eight articles described ocular
findings among cohorts of ZIKV-infected neonates.
16–23
Postnatal ocular abnormalities were found in almost one-
2A. MAHMOUD ET AL.
quarter of infected children (305/1291, 23.6%). Table 2 sum-
marizes the most frequently reported features: pigmentary
changes (169/1291, 13%), optic nerve atrophy (161/1291,
12.4%), macular chorioretinal atrophy (157/1291, 12.1%),
increased cup-to-disk ratio (154/1291, 11.6%), optic nerve
hypoplasia (71/1291, 5.4%), vascular changes (21/1291,
1.6%), retinal coloboma (16/1291, 1.2%), hemorrhagic reti-
nopathy (16/1291, 1.2%), and strabismus (10/1291, 0.7%).
Microphthalmia and cataract were found in 0.6% (8/1291)
and 0.2% (3/1291) of cases, respectively. Lens subluxation
and congenital glaucoma were found in only one case
(1/1291).
Descriptions of all postnatal ocular findings among neonates
with ocular damage due to ZIKV infection are shown in Table 3.
The posterior segment of the eye is more affected than the ante-
rior segment. Posterior segment abnormalities included pigmen-
tary changes (229/479, 47.8%), macular chorioretinal atrophy
(216/479, 45%), optic nerve atrophy (181/479, 37.8%), increased
cup-to-disk ratio (190/479, 39.6%), optic nerve hypoplasia
(93/479, 19.4%), vascular changes (26/479, 5.4%), and retinal
coloboma (20/479, 4.1%). Lesions are therefore often associated
with the retina along with choroid and optic nerves to varying
degrees.
Abnormalities of visual function and extrinsic ocular moti-
lity were described in five articles
17,21,26,34,39
and consisted of
refractive errors (92/479, 19.2%), nystagmus (45/479, 9.3%),
and strabismus (89/479,18.5%). Anterior segment anomalies
include cataract (9/479, 1.8%), lens subluxation (1/479, 0.2%),
iris coloboma (5/479, 1%), and congenital glaucoma (7/479,
1.4%). Microphthalmia was found in 13 cases (2.7%) which
were constantly associated with other ocular anomalies. These
ocular anomalies were rarely isolated (1/479, 0.2%).
28
Extraocular findings were assessed in 455 neonates (Table 4),
the most common finding was microcephaly which was
observed in 90% of cases (410/455, 90.1%).
In some cases, microcephaly was associated with other CNS
disorders such as parenchymal calcifications (57/455, 12.5%),
ventriculomegaly (22/455, 4.8%), and cerebellar hypoplasia
(12/455, 2.6%) or more rarely with bone disorders such as
arthrogryposis (9/455, 1.9%). Among cohorts of infants with
Figure 1. Study inclusion flow diagram showing the search and study selection strategies according to preferred reporting items for systematic reviews and Meta‐
Analyses guidelines.
11
OCULAR IMMUNOLOGY AND INFLAMMATION 3
ocular lesions,
17,18,20,24,26,28,35,37,39
microcephaly was found in
86.8% (284/327) of cases.
Term of pregnancy at the onset of maternal infection was
available in 194 cases. Ocular anomalies had occurred after
maternal ZIKV infection during the first trimester of preg-
nancy in 102 cases (52.5%), in the second trimester in 40 cases
(20.6%), and in the third trimester in 8 cases (4.1%).
Progression of congenital ocular damage
A few articles with heterogenous populations have described
the evolution of ocular damage after it was first identified
during the initial ophthalmological examination. Follow-up of
ocular lesions was available in 119 fetuses
20,33,36,39
with ocular
damage due to congenital ZIKV infection. Among them, 58
cases reported by Tsui et al.
20
and Guevara JG et al.
36
were
reevaluated after 3 months of follow-up and showed no new
lesions or signs of activity of lesions prior to initial examination.
In contrast, de Paula Freitas et al.
33
documented an aggravation
of ocular lesions in a neonate with congenital glaucoma due to
ZIKV infection. They report buphthalmia and enlargement of
the horizontal diameter of the cornea after 95 days of follow-up.
In a cohort of 60 children with visual impairment due to ZIKV
infection, Ventura Lo et al.
39
evaluated the visual response to
correction of refractive error and hypoaccommodation. Despite
some eyes being structurally damaged, immediate improvement
in binocular vision was observed in 62% of cases. The authors
suggest a positive response to early treatment in children with
ocular abnormalities due to ZIKV infection.
Ocular histopathologic features in congenital Zika
syndrome
Only one study has described ocular histopathologic features
associated with congenital Zika syndrome.
15
Ocular tissue
samples from four cases of voluntary termination of pregnancy
with associated congenital Zika syndrome showed thinning of
the photoreceptor layer, retinal pigment epithelium (RPE) and
choroid, perivascular choroidal inflammatory infiltrate, and
optic nerve atrophic changes in all specimens. Ocular ultra-
sonographic abnormality was reported only in one case with
microcalcifications located in the retina. Zika virus antigen
expression was detected in the retina, choroid, and optic
nerve.
15
OCT imaging abnormalities in congenital Zika syndrome
Four articles shown in Table 5 investigated OCT results in
congenital ZIKV cases.
28,31,37,38
Severe damage of the neuro-
sensory retina and choroid were reported. OCT in 13 neonates
with congenital Zika virus infection showed tomographic
abnormalities in almost all cases. Only one infant (1/13,
7.6%), reported by de Oliveira,
23
had normal OCT findings
despite the presence of a bilateral macular pigment mottling
lesion. The most common OCT findings were: hyperreflectiv-
ity underlying the RPE (11/13, 76.9%), interruption of the
ellipsoid zone (10/13, 76.9%), retinal thinning (10/13, 76.9%),
choroidal thinning (6/13, 46.1%), colobomatous-like excava-
tion (6/13,46.1%), and subretinal cleft (1/13, 7.6%).
Discussion
Main ndings
This review illustrates the wide spectrum of visual impairment
caused by congenital Zika virus infection that involves both
ocular structural damage and CNS alterations. These abnorm-
alities mostly tend to occur after first and second trimester
infections and are rare afterwards. Ocular finding is often
associated with other central nervous system abnormalities.
Ocular calcifications, microphthalmia, and cataract are the
Table 1. Ultrasonographic ocular abnormalities reported in the antenatal period with associated extra-ocular findings in congenital Zika virus syndrome.
First
author, year
Number
of cases
Weeks of
gestation at
maternal
infection
Weeks of
gestation at
US diagnosis
Ocular ultrasound
findings Extra-ocular ultrasonographic findings Outcomes
Oliveira Melo
9
1 Unknown 29.2 Intraocular
calcifications,
bilateral
cataract
and
microphthalmia
Microcephaly, ventriculomegaly, corpus callosum not visualized,
thalami not developed, thin pons and brainstem, non-
homogeneous small mass seen at position of basal ganglia,
lateral ventricles and fourth ventricle calcifications
Unknown
Carvalho
12
1 9 22 Ocular
calcifications,
Microcephaly, parenchymal calcifications, Dandy Walker
malformation, arthrogryposis
Neonatal
death, CS at
37 weeks
Melo AS
13
1 20 29 Microphthalmia Microcephaly, reduced cerebral volume and subcortical
calcifications, ventriculomegaly, brainstem hypoplasia,
cerebellum hypoplasia
Neonatal
death at 41
weeks
L. Pomar
14
2 15 19 Severe bilateral
microphthalmia
Severe microcephaly, cerebellar
hypoplasia/large cisterna magna, polyhydramnios
Delivery at 32
weeks
15 Unknown Ocular
calcifications
Microcephaly, cerebellar
hypoplasia/large cisterna magna,
ventriculomegaly, callosal hypoplasia, parenchymal
calcifications, liver calcifications
Unknown
Fernandez
MP
15
1 Unknown 30 Retinal
calcifications
Microcephaly, frontal lobe hypoplasia, craniosynostosis,
parenchymal calcifications
Voluntary
termination
of
pregnancy
US, ultrasound; CS, cesarean section.
4A. MAHMOUD ET AL.
Table 2. Prevalence of ocular damage among a cohort of ZIKV-infected fetuses.
First author,
year
Number
of cases
Ocular
findings
Micro-
phthalmia
Refractive
errors Nystagmus Strabismus Cataract
Lens
subluxation
Iris
Coloboma
Congenital
glaucoma
Increased
cup-to-
disk ratio
Optic
nerve
atrophy
Optic
nerve
hypoplasia
Pigmentary
changes
Macular
Chorioretinal
atrophy
Torpedo
maculopathy
Retinal
coloboma
Vascular
changes
Hemorrhagic
retinopathy
Macular
scar
Hcini N
16
10 3 1 2 1
Zin AA
17
112 24 1 6 11 11 7 6 1 4
Ventura CV
18
469 148 5 3 1 1 93 122 36 112 101 13 20
De Paula
19
29 10 1 1 6 2 8 8
Tsui I
20
224 57 1 1 35 12 12 20 22 2 1
Verçosa I
21
77 25 1 10 10 18 15
Ventura CV
22
40 24 9 6 14 11 3
Merle H
23
330 14 1 1 11 2
Total
Percentage (%)
1291 305 8 0 7 10 3 1 4 1 154 161 71 169 157 1 16 21 16 2
23.6 0.6 0 0.5 0.7% 0.2 0.07 0.03 0.07 11.9 12.4 5.4 13.1 12.1 0.07 1.2 1.6 1.2 0.15
OCULAR IMMUNOLOGY AND INFLAMMATION 5
Table 3. Description of postnatal ocular findings in ZIKV-infected fetuses with at least one ophthalmic abnormality.
First author,
year
Number
of cases
Micro-
phthalmia
Refractive
errors Nystagmus Strabismus Cataract
Lens
subluxation
Iris
Coloboma
Congenital
glaucoma
Increased
cup-to-disk
ratio
Optic
nerve
atrophy
Optic nerve
hypoplasia
Pigmentary
changes
Macular
Chorioretinal
atrophy
Torpedo
maculopathy
Retinal
coloboma
Vascular
changes
Hemorrhagic
retinopathy
Macular
scar
Hcini N
16
3 1 2 1
Zin AA
17
24 1 6 11 11 7 6 1 4
Ventura
18
148 5 3 1 1 93 122 36 112 101 13 20
De Paula
19
10 1 1 6 2 8 8
Tsui I, 2018
20
57 1 1 35 12 12 20 22 2 1
Verçosa I
21
25 1 10 10 18 15
Ventura CV
22
24 9 6 14 11 3
Merle H
23
14 1 1 11 2
De Paula FB
24
6 4 5 1 1 2
Culjat M
25
1 1 1 1
Ventura LO
26
32 32 9 24 6 5 5 9 11 2
Ventura CV
27
3 3 3
Mesnard C
28
1 1
de Miranda HA
29
3 3 2 2 1
Yepez JB
30
43 5 5 27 11
de Oliveira D
31
2 1 1 2 1 1 1
Ventura CV
32
1 1
De Paula FB
33
1 1 1 1 1
Ventura CV
34
10 1 4 3 5 7 3
Ventura CV
35
1 1
Guevara JG
36
1 1 1 1
Ventura CV
37
8 1 1 1 5 8
Campos AG
38
1 1
Ventura LO
39
60 1 60 28 55 1 19 9 7 17 26 1
Total
Percentage (%)
479 13 92 45 89 9 1 5 7 190 181 93 229 216 4 20 26 16 11
2.7 19. 9.3 18.5 1.8 0.2 1 1.4 39.6 37.8 19.0 47.8 45 0.8 4.1 5.4 3.3 2.2
6A. MAHMOUD ET AL.
most frequently reported antenatal ophthalmic abnormalities.
These ocular findings can be bilateral
9,14
or unilateral.
13
The
spectrum of ocular lesions in ZIKA-infected fetuses correlates
with the embryological stages of ocular development that
occur during the first trimester.
40,41
Microphthalmia appears
to be the consequence of an altered mechanism of embryogen-
esis by the teratogenic effect of the virus in the early embryo-
genic stage,
24
while other lesions such as cataracts, congenital
glaucoma, macular chorioretinal atrophy, and pigmentary
mottling are the consequence of the rupture of the blood-
retinal barriers as well as the blood-aqueous barriers by the
virus. The presence and the replication of ZIKV in ocular
tissues can induce an immune-mediated inflammation that
may occur later in pregnancy.
42
Many lesions observed in the
neonatal period may be diagnosed prenatally if a dedicated
examination of the eyeball using high-frequency ultrasound or
MRI is performed.
The follow-up of ocular lesions seems to be unchanged with
possible long-term visual impairment and worsening of some
lesions. In contrast to other arboviruses such as West Nile
Table 4. Postnatal extra-ocular abnormalities in cases of congenital Zika virus.
First
author, year Extraocular findings
Illness during pregnancy (trimester)
Number of cases
First
trimester
Second
trimester
Third
trimester
Unknown
time
Zin AA
17
Microcephaly (14/24, 58.3%)
Ventriculomegaly, cerebral calcifications (16/24, 66.7%) Arthrogryposis
(7/24, 29.2%)
24 14 8 2
Ventura CV
18
Microcephaly (129/148, 87%) NA
De Paula FB
19
Microcephaly (10/10, 100%) NA
Tsui I
20
Microcephaly (52/57,91.2%) 44 out of 57 34 9 1
Vercosa I
21
Microcephaly (25/25, 100%) 19 out of 25 15 4
Ventura CV
22
Microcephaly (24/24, 100%) 14 out of 24 10 3 1
Merle H
23
NA NA
De Paula FB,
24
Microcephaly (4/6, 66%) 5 out of 6 2 2 1
Culjat M
25
Microcephaly, ventriculomegaly,
cerebral calcifications (1/1, 100%)
1 1
Ventura LO
26
Microcephaly (29/32, 91%)
Cerebellar hypoplasia (12/32,37.5%)
Cerebral calcification (31/32, 96.8%)
26 out of 32 13 9 3 1
Ventura CV
27
Microcephaly (3/3, 100%) Cerebral calcifications (3/3, 100%) 1 out of 3 1
Mesnard C
28
No systemic anomalies No symptoms
de Miranda
HA
29
Microcephaly (3/3, 100%) 3 3
Yepez JB
30
Microcephaly (43/43, 100%) 43 43
de Oliveira D
31
Microcephaly, ventriculomegaly (2/2, 100%) Corpus callosum agenesis,
cerebral calcification (1/2, 50%)
No symptoms
Ventura CV
32
Cerebral calcifications and ventriculomegaly (1/1, 100%) No symptoms
De Paula FB
33
Microcephaly, arthrogryposis, ventriculomegaly, diffuse parenchymal
calcifications (1/1, 100%)
No symptoms
Ventura CV
34
Microcephaly (10/10, 100%) 7 out of 10 6 1
Ventura CV
35
Cerebral calcifications 1 1
Guevara JG
36
Microcephaly, ventriculomegaly arthrogryposis
(1/1, 100%)
No symptoms
Ventura CV
37
Microcephaly (7/8, 100%)
Cerebral calcifications (1/8, 12.5%)
6 out of 8 2 4
Campos AG
38
Microcephaly (1/1, 100%)
Cerebral calcifications (1/1, 100%)
Ventriculomegaly (1/1, 100%)
No symptoms
Ventura LO
39
Microcephaly (51/60, 85%) NA
Total Microcephaly (410/455, 90.1%)
Parenchymal calcifications (57/455, 12.5%)
Ventriculomegaly (22/455, 4.8%
Cerebellar hypoplasia (12/455, 2.6%)
Arthrogryposis (9/455, 1.9%)
Symptoms: 194/
237 (81.7%)
102/194
(52.5%)
40/194
(20.6%)
8/194
(4.1%)
44/194
(22.6%)
NA, not assessed.
Table 5. Optical coherence tomography imaging abnormalities in congenital Zika virus-infected neonates.
First author
Number of
cases
Hyperreflectivity
underlying the
RPE
Outer retina
thinning
Ellipsoid zone
interruption
Choroidal
thinning
Colobomatous-like
excavation
Subretinal
cleft
Ventura et al.
37
8 8 8 8 6 4
Campos et al.
38
1 1 1 1 1
De Oliveira et al.
31
2 1 1 1
Mesnard et al.
28
1 out of 2 1 1 1
Total 12 out of 13 11/13
(84.6%)
10/13
(76.9%)
10/13 (76.9%) 6/13
(46.1%)
6/13
(46.1%)
1/13
(7.6%)
RPE, retinal pigment epithelium.
OCULAR IMMUNOLOGY AND INFLAMMATION 7
virus, no reactivation of ZIKV-induced eye lesions was
observed.
43
It is still paramount to offer systematic and meth-
odological ocular ultrasound screening in the antenatal period
and conduct long-term ophthalmic follow-up of Zika-exposed
newborns.
However, in adults, only rare inflammatory lesions such as
such conjunctivitis, anterior uveitis, acute unilateral maculo-
pathy, and chorioretinitis were observed.
44–48
Discovery of eye lesions due to ZIKV infection in the
antenatal period appears to be more severe and with high
risk of visual impairment. Damage related to ZIKV infection
is mostly due to the teratogenic effects of the virus rather than
its presence in fetal eye tissue. Thus, in the neonatal period, all
in utero-exposed newborns must be evaluated for ocular
impairment and long-term follow-up for ocular abnormalities
is crucial.
Strengths and limitations
To our knowledge, this is the first systematic review to address
the ophthalmological consequences of congenital zika virus
infection. Furthermore, this review involved
a multidisciplinary team of obstetricians, fetal-medicine spe-
cialists, and ophthalmologists. We included numerous original
articles published over a long period. The results of this review
should be interpreted with caution because of limitations.
First, in this study, the most included articles were cases series
with small sample sizes, poor study design and publication
bias. Indeed, among the 112 articles on the subject “ocular
abnormalities congenital zika virus” only 31 described detailed
antenatal or postnatal signs of congenital zika virus. Among
them, antenatal ultrasound findings were rarely specified.
Second, correlation between antenatal ultrasound and postna-
tal ocular finding was not studied. Few articles have precisely
described the ocular antenatal ultrasound findings. Most arti-
cles have focused on nervous central system and microcephaly
rather than ocular ultrasonographic abnormality. When
described, authors lack precisions in methods of measure and
assessment of abnormalities. For example, cases of micro-
phthalmia are poor described with lack of precision when
using preestablish nomograms. Some methods for assessing
fetal eyes are inappropriate as using orbital total axe length to
conclude to microphthalmia. In this context, craniosynostosis
due to ZIKV can associate small orbit bur normal eye length.
49
Finally, study of progression of lesions remains difficult
because most of article did not report the evolution of lesions
in the same fetuses and child. Most of children with severe
antenatal ocular lesions lacked ophthalmic screening and fol-
low-up. In fact, articles are heterogeneous, and the study
population is varying. We think that this bias is due to the
rapidity and brutality of the outbreak that did not allow clin-
ician and researchers to provide large scale studies. Many cases
had inadequate antenatal exploration or lacked complete fol-
low-up.
Results in the context of what is known
In view of the threat of Zika virus outbreak, especially con-
genital Zika syndrome, the lack of literature in this field is
alarming. More than 87 countries and territories were affected
by the ZIKV epidemic during the 2015–2016 outbreak, with
more than 500,000 cases reported at the peak of the pandemic
in 2016.
50
Due to the lack of diagnostic tools, the real number
of cases is largely underestimated in pandemic areas.
51
The
cumulative risk of ZIKV infection for the young and pregnant
women living in epidemic areas has been estimated to be from
21 to 63%.
52,53
Correlations between adverse outcomes and gestational age
at the time of maternal ZIKV infection were poorly described
and therefore remain unclear. The severity of lesions is directly
related to the gestational age. In particular, the first trimester
has the greatest risk for fetal abnormalities.
Few articles described fetal eye anomalies due to the
ophthalmic antenatal lesions of ZIKV, while most focused on
microcephaly and CNS alterations. As the starting point for
ophthalmological lesions is certainly the antenatal period,
ocular antenatal lesions deserve greater attention and commu-
nication with an ophthalmologist. This study confirmed that
many early neonatal lesions are amenable to prenatal diagno-
sis. Early detection of lesions enables timelier follow-up and
management, which was associated with better prognosis.
54
In a recently published report, the proportion of birth
defects in pregnant women infected with ZIKV was shown to
be 20 times higher than in the normal population.
54
ZIKV has
neuropathogenic and teratogenic effects in the eyes. It shares
theses proprieties with other arboviruses such as West Nile
virus.
55
It was suggested that linear, radial, or curvilinear
arrangement of chorioretinal lesions seems to follow the archi-
tecture of retinal fibers, suggesting neurogenic rather than
hematogenous propagation of West Nile virus to the choroid
and retina. Clinicians should be aware that these anomalies are
nonspecific and can also mimic the signs of other TORCHS
17
infections (i.e., Toxoplasmosis, Rubella, Cytomegalovirus,
Herpes simplex virus, Syphilis), which should also be investi-
gated. For example, cataracts and microphthalmia were
reported in congenital rubella syndrome.
56
In a cohort of 27
neonatal-onset bilateral congenital glaucoma cases reported by
Kaushik et al.,
57
25.9% were rubella-IgM positive. Fetal catar-
act was reported in congenital toxoplasmosis.
58
Ophthalmic
manifestations of intrauterine cytomegalovirus infection can
include chorioretinitis, optic nerve colobomas, and corneal
opacities.
59
Ophthalmic abnormalities, such as cataracts, can
also result from genetic or chromosomic disorder.
60,61
This review shows that ZIKV may be responsible for a wide
range of ocular manifestations that could be present in 23.6%
of newborns presenting a congenital ZIKV infection. There is
a strong association between microcephaly and ZIKV-
associated ocular lesions with almost 86.8% of newborns show-
ing eye abnormalities. However, absence of microcephaly
should not delay screening for ocular anomalies, as 13.2% of
newborns with ocular anomalies did not have microcephaly.
Special attention should be paid to the interpretation of post-
natal ocular abnormalities. Some reported lesions, such as
retinal hemorrhages, may be frequently present in premature
babies and after obstetric trauma.
62
In view of our results, the occurrence of infection in the first
trimester and the presence of microcephaly are major risk
factors associated with ocular manifestations and long-term
8A. MAHMOUD ET AL.
visual impairment. In the neonatal period, the retina and optic
nerve are the most affected structures following ZIKV infec-
tion. OCT analysis showed similarities between clinical fea-
tures and ocular results that include thinning of the sensory
retina, interruption of the ellipsoid zone, and underlying
hyperreflectivity of the pigment epithelium. However, some
clinical signs are not detectable by OCT such as pigmentary
changes. These findings are supported by histopathological
studies after medical termination of pregnancy showing thin-
ning of pigment epithelium, neurosensorial retina and chor-
oid, and pigment loss. Immunohistochemical studies
demonstrated Zika virus antigen expression in the retina,
choroid, and optic nerve.
28,31,37,38
Clinical features, OCT ana-
lysis, and histopathological studies highlight both the neuro-
tropism of ZKV and the devastating effect of this virus on
retinal tissue and the optic nerve.
Research and clinical implications
This review supports the fact that in utero ZIKV exposure is
associated with fetal ocular adverse outcomes. Congenital Zika
syndrome is a serious disease and requires multidisciplinary
care. Antenatal ocular abnormalities, such as microphthalmia,
cataract, and intraocular calcifications, can be an early warning
sign of a ZIKV-infected fetus. The presence of microcephaly is
a poor prognostic factor for visual impairment. Prenatal exam-
ination of the fetal eye must therefore be systematic, methodi-
cal, and standardized in pregnant women exposed to the Zika
virus regardless of the presence of microcephaly. Ocular
assessment must be initiated in the antenatal period with
collaboration between ultrasound specialists and
ophthalmologists.
Ultrasound screening of exposed fetuses must include lens
evaluation, axial eye length comparison, optic nerve and
chiasm evaluation, and screening for intraocular calcifications.
Ultrasound examinations should be repeated as necessary and
discussed with the ophthalmologist. All lesions discovered in
the antenatal period must be checked and monitored in the
neonatal period. Clinicians should be aware that these anoma-
lies are nonspecific and can also mimic the signs of other
TORCHS infections which must be excluded using serological
and invasive testing if necessary. Introduction of the higher
frequency transducer probe with various three-dimensional
imaging modes in recent years has considerably improved
image resolution.
Traditionally, the search for microphthalmia is based on the
measurement of the bi-orbital diameter (BOD) is defined as
the distance between the two malar margins
63
and the orbital
diameter (OD) which defines the distance between the eth-
moidal and malar margins of the eyeballs.
64
Congenital ZIKV has been associated with early fusion of
sutures resulting in craniosynostosis.
3
Craniosynostosis can
lead to a reduction in orbital volume without necessarily
altering eyeball size.
65
Therefore, emphasis should be placed
on measurement of the total axial length of the globe and
not the orbits. To measure the distance of total axial length,
calipers are positioned on the lines between the most ante-
rior point of the cornea and the junction between the vitr-
eous body and the retina, crossing the center of the eyeball.
66
Measurements are ideally made within the axial plane, with
both orbits of equal and largest possible diameter.
66
Microphthalmia is suspected when axial length is two stan-
dard deviations below the population mean-adjusted value
for gestational age.
67
Pathologies discovered during the prenatal examination
must be confirmed in the early neonatal period, treated if
possible, and followed-up into adulthood. Failures or delays
in diagnosis can lead to irreversible ocular sequelae in cases of
congenital glaucoma and cataract. This recommendation may
also be applied for many other infections, such as toxoplasmo-
sis and rubella. Ocular anomalies must be considered in
a general context, and multidisciplinary collaboration is crucial
in cases of fetal infection, especially among ophthalmologists
and obstetricians. This must necessarily involve international
cooperation to improve biological diagnosis and imaging
resources in low-income countries, which are often more
affected by these outbreaks.
Conclusions
The dramatic consequences of the recent ZIKV pandemic
have highlighted the threat that emergent pathogens may
represent for the unborn child. Climate change will foster
the re-emergence of ZIKV and other arboviruses, as well as
their spread to geographical areas not yet affected. Arbovirus
infections can be potentially more serious in fetuses by
increasing the risks of neurological disorders and neurosen-
sorial impairments. In this context, ophthalmic assessment
should be systematic and employed using standardized
methods within a multidisciplinary team approach. In the
absence of effective vaccines, prevention is essentially depen-
dent upon the individual and must be emphasized during
pregnancy, particularly during the first trimester that has the
highest risk. Pregnant women and their partner(s) should
practice caution when considering travel to endemic areas.
Further large-scale cohort studies during outbreaks are
required to evaluate the natural history of ocular manifesta-
tions of congenital ZIKV infections and their progression
during childhood.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The author(s) reported there is no funding associated with the work
featured in this article.
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