Congenital Zika syndrome

Abstract

In February 2016, the World Health Organization declared Zika virus (ZIKV) infection a public health emergency of international concern because it caused congenital Zika syndrome (CZS). The CZS is considered a specific pattern of birth defects caused by ZIKV infection, which is transmitted by the bite of the Aedes aegypti mosquito. The CZS clinical manifestations are broad and nonspecific, including microcephaly, subcortical calcifications, ocular alterations, congenital contractures, early hypertonia, and pyramidal as well as extrapyramidal symptoms. The ZIKV has gained great importance because it has affected a large percentage of the population worldwide during the last few years, despite the measures implemented by international organizations. The pathophysiology and non-vectorial transmission routes of the virus are still under study. The diagnosis is made upon suspicion of ZIKV infection, the patient’s clinical manifestations, and it is confirmed by molecular laboratory tests demonstrating the presence of viral particles. Unfortunately, there is no specific treatment or vaccine for this condition; however, patients receive multidisciplinary care and constant monitoring. Therefore, the strategies that have been implemented are directed toward preventive measures and vector control.

Full text

3
Congenital Zika syndrome
Israel E. Crisanto-López1,2, Pablo López-De Jesús2,3, Jacqueline López-Quecho4, and
Juan C. Flores-Alonso2*
1Dirección General de Calidad y Educación en Salud, Secretaría de Salud, Mexico City; 2Centro de Investigación Biomédica de Oriente, Instituto
Mexicano del Seguro Social, Atlixco, Puebla; 3Programa de Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana,
Mexico City; 4Universidad Popular Autónoma del Estado de Puebla, Facultad de Medicina, Puebla, Mexico
Boletín Médico del
Hospital Infantil de México
REVIEW ARTICLE
Abstract
In February 2016, the World Health Organization declared Zika virus (ZIKV) infection a public health emergency of interna-
tional concern because it caused congenital Zika syndrome (CZS). The CZS is considered a specific pattern of birth defects
caused by ZIKV infection, which is transmitted by the bite of the Aedes aegypti mosquito. The CZS clinical manifestations are
broad and nonspecific, including microcephaly, subcortical calcifications, ocular alterations, congenital contractures, early
hypertonia, and pyramidal as well as extrapyramidal symptoms. The ZIKV has gained great importance because it has affec-
ted a large percentage of the population worldwide during the last few years, despite the measures implemented by inter-
national organizations. The pathophysiology and non-vectorial transmission routes of the virus are still under study. The
diagnosis is made upon suspicion of ZIKV infection, the patient’s clinical manifestations, and it is confirmed by molecular
laboratory tests demonstrating the presence of viral particles. Unfortunately, there is no specific treatment or vaccine for this
condition; however, patients receive multidisciplinary care and constant monitoring. Therefore, the strategies that have been
implemented are directed toward preventive measures and vector control.
Keywords: Zika virus. Congenital Zika syndrome. Microcephaly.
Síndrome congénito por virus Zika
Resumen
En febrero de 2016, la Organización Mundial de la Salud declaró a la infección por virus Zika una emergencia de salud pública
de importancia internacional por ser la causa del síndrome congénito por virus Zika. Este síndrome es considerado un patrón
específico de defectos al nacimiento causados por la infección por virus Zika, que se transmite por la picadura del mosquito
vector Aedes aegypti y cuyas manifestaciones clínicas son amplias e inespecíficas, entre las que destacan microcefalia, calci-
ficaciones subcorticales, alteraciones oculares, contracturas congénitas, hipertonía temprana y síntomas de afectación piramidal
y extrapiramidal. Este virus ha tomado gran importancia debido a que durante los últimos años ha afectado a un gran porcen-
taje de la población en todo el mundo, a pesar de las medidas implementadas por organizaciones internacionales. La fisiopa-
tología y las vías de transmisión no vectorial de la infección aún siguen en estudio. El diagnóstico se realiza ante la sospecha
por las manifestaciones clínicas del paciente, y se confirma mediante pruebas moleculares de laboratorio en las que se
demuestre la presencia de partículas virales. Desafortunadamente, no existe aún un tratamiento ni una vacuna específica para
*Correspondence:
Juan C. Flores Alonso
E-mail:juan.oresal@imss.gob.mx
Available online: 27-02-2023
Bol Med Hosp Infant Mex. 2023;80(1):3-14
www.bmhim.com
Date of reception: 08-07-2022
Date of acceptance: 18-10-2022
DOI: 10.24875/BMHIM.22000110
1665-1146/© 2022 Hospital Infantil de México Federico Gómez. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Bol Med Hosp Infant Mex. 2023;80(1)
Introduction
Congenital Zika syndrome (CZS) is considered a
specic pattern of newborn defects caused by Zika
virus (ZIKV) infection, a microorganism that has been
considered a teratogenic agent1-3. Although the patho-
physiological pathways by which this infection causes
organ dysfunction are still under investigation, nervous
system, musculoskeletal and visual impairment have
been described in infected newborns. The following
clinical manifestations stand out: microcephaly with
subcortical calcications, retinal alterations, congenital
contractures, early hypertonia, and extrapyramidal
symptoms, which can occur together or separately in
each patient4,5.
ZIKV infection has become very important in recent
years because it is associated with signicant health
problems worldwide and has been classied as a public
health emergency of international concern6. This has
prompted various international organizations such as
the World Health Organization (WHO), the United
States Centers for Disease Control and Prevention
(CDC), and the Pan American Health Organization
(PAHO) to take preventive measures to avoid its further
progression as a pathological entity6 -8.
In October 2015, the Secretaría Estatal de Salud
(State Health Secretariat) of Pernambuco, Brazil,
reported 26 cases of microcephaly associated with
ZIKV infection8,9. Subsequently, countries worldwide
began to report cases of patients with microcephaly
and infection with serum ZIKV viral load. ZIKV infection
during pregnancy was found to cause CZS and com-
plications during pregnancy, such as preterm labor or
even spontaneous abortion5,10.
In Mexico, epidemiological surveillance has been
conducted through the Secretaría de Prevención y
Promoción a la Salud (Secretariat of Prevention and
Health Promotion). According to the information bulletin
“Conrmed cases of ZIKV disease” for the 52ndepide-
miological week of 2021, 12,991cases of ZIKV infection
were reported from 2015 to December 31, 2021, with
Veracruz, Yucatán, and Nuevo León being the states
with the highest number of conrmed cases. In addi-
tion, it was reported that 7152 pregnant patients pre-
sented ZIKV infection, with Yucatán having the highest
number of cases with 926, followed by Veracruz with
888 cases and Tamaulipas with 692 cases11. In addi-
tion, 44 cases conrmed by epidemiological associa-
tion of CZS and 56 laboratory-conrmed cases of CZS
were reported12,13.
At present, the diagnosis of ZIKV disease in rst-contact
health services is complicated due to the similarity of the
clinical picture with diseases caused by other viruses of
the same genus, such as Dengue and Chikungunya
virus14-16 (Table1). Symptoms are generally mild, lasting
2-7 days, and may consist of fever, rash, conjunctivitis,
muscle and joint pain, malaise, and headache; however,
most infected patients are asymptomatic8.
ZIKV
The virus was named after the Zika forest in Entebbe,
Uganda, Africa, where it was discovered in 1947 in
rhesus monkeys, in which transmission was only enzo-
otic, restricted to primate-mosquito circulation17,18.
Subsequently, the rst case of human transmission
was reported in 1954 in a 10-year-old Nigerian girl who
had a serum viral load of ZIKV. However, it was difficult
to relate her clinical presentation to ZIKV infection
because parasites of the genus Plasmodium were also
found in her blood samples19. In the same year, two
more cases of ZIKV infection in humans were reported,
conrmed by increased serum-neutralizing antibodies20.
In 1966, ZIKV infection was massively detected in the
Asian population, which increased research on human
transmission. As a result, the ability of the virus to infect
humans through a vector was reported, and its wide
geographical distribution and the presence of different
viral lineages, both from the African and Asian conti-
nents, were demonstrated21. Subsequent studies
showed that ZIKV is an arbovirus of the genus
Flavivirus, whose main vector is the Aedes aegypti
mosquito1. Since then, cases of ZIKV infections in
humans with diverse clinical manifestations have been
reported; over time, cases with more severe alterations
have appeared5,15,22.
Subsequently, a high incidence of cases was reported
in 2007 on the islands of Yap in Micronesia23, and in
2008 the rst cases of sexual transmission were
reported24. In 2013 and 2014 in French Polynesia, the
rst cases of ZIKV infection were reported with
este padecimiento; sin embargo, los pacientes reciben cuidados multidisciplinarios y monitorización constante. Las estrategias
que se han implementado se dirigen hacia medidas preventivas de la infección y el control de los vectores.
Palabras clave: Virus Zika. Síndrome congénito por virus Zika. Microcefalia.

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I.E. Crisanto-López et al. Congenital Zika syndrome
post-infectious onset of Guillain-Barré syndrome,
maternal-fetal transmission, and the presence of viral
load in semen samples from asymptomatic donors25.
In the Americas, it is estimated that ZIKV was intro-
duced between May and December 2013; however, the
rst reported cases of CZS were in May 2015 in Brazil,
attributed to globalization and migratory movements
due to social and sporting events5,26,27.
The worldwide spread of the virus was rapidly pro-
gressive, and cases began to be documented in sub-
tropical areas, Central and North America, and 87
countries of different geographic distribution. More than
500,000cases were reported worldwide. This prompted
the WHO to declare ZIKV infection as a Public Health
Emergency of International Concern on February 1,
2016, and temporarily conrmed the association of
ZIKV infection with microcephaly, Guillain-Barré syn-
drome, sexual, blood and vertical transmission, as well
as the occurrence of severe birth defects in neonates
with parents with a history of ZIKV infection5-7,20.
ZIKV belongs to the Flavivirus genus of the
Flaviviridae family and measures approximately 40
nanometers (nm) in diameter. Its genetic material
corresponds to a single-stranded ribonucleic acid chain
(single-stranded RNA) of positive polarity, which
encodes a polyprotein whose translation gives rise to
three structural proteins: capsid protein (C), membrane
precursor (prM) and envelope protein (E), and 7
non-structural proteins (NS): NS1, NS2A, NS2B, NS3,
NS4A, NS4B, and NS528. The function of each of these
is described in Ta b le2.
The viral particle consists of a symmetric icosahedral
structure with a viral envelope containing the E and M
proteins as molecules for attachment and host cell rec-
ognition (Fig.1A)26,29. The entry of ZIKV into the host
cell is mediated by the E protein, which allows attach-
ment and fusion to the specic receptors TIM1, TYRO-
3, and AXL, thus activating the endocytosis processes
and the entry of the virion into the cell cytoplasm29,30.
Inside the cell, non-structural proteins bind to the
endoplasmic reticulum (ER), forming a complex that
allows replication and assembly of viral RNA called
viroplasm31. This involves NS4A and the formation of
ER invaginations in which NS1 subsequently acts to
initiate the viral genome replication processes, and
NS3 RNA helicase and NS5 polymerase act, assisted
Table1. Main clinical manifestations in Zika, dengue and Chikungunya virus infections
Signs and symptoms Zika Dengue Chikungunya
Reason for consultation Exantema o prurito Fever, myalgia Joint pain, fever
Fever Mild Moderate Intense
Very infrequent Very frequent Very frequent
Duration: 1‑3 days Duration: 5‑7 days Duration: 5‑7 days
Exanthema and features Typically from day 1 Appears from 5th to 7th day Appears on the 2nd or 3rd day
Maculopapular, cephalo‑caudal Not characteristic Not characteristic
Pruritus Moderate to intense Mild to severe Mild to moderate
Conjuntivitis Very frequent Infrequent Adults: Very rare/Children: Very common
Neurological
manifestations
Possible and serious Infrequent Infrequent (can be frequent and severe
in newborns)
Headache Mild to moderate Intense and frequent Mild to moderate
Retro‑orbital pain Infrequent Intense and frequent Infrequent
Polyarthralgia Frequent Absent Very frequent
Polyarthritis Frequent Absent Frequent
Myalgia Infrequent Very frequent and intense Frequent, moderate to severe
Diarrhea Very infrequent Frequent Very infrequent
Skin bleeding Very infrequent Frequent Very infrequent
Mucosal bleeding Very infrequent Alarm sign Very infrequent (severe when present)

6
Bol Med Hosp Infant Mex. 2023;80(1)
by NS4B. Viral packaging requires the action of NS2A
and NS2B through viral RNA packaging vesicles. In
these vesicles, the structural proteins are integrated, a
process necessary for their transport into the cell,
mainly through the interaction of the E protein and prM
with the Golgi apparatus28,31,32. At the same time, ZIKV
generates modications in centrosomes to reorganize
microtubules and facilitate their transport and intracel-
lular propagation33,34. Subsequently, for viral release
into the extracellular environment, it was described that
ZIKV can induce a process of apoptosis mediated by
autophagy, processes of degranulation of viral RNA
packaging vesicles, or processes of exocytosis34. The
NS5 viral protein antagonizes the type I interferon
response to favor viral dissemination. This leads to
proteasomal degradation of STAT2 (a transcription fac-
tor that generates chain responses of the immune sys-
tem), allowing ZIKV to inltrate the lymphatic and
circulatory system, which leads to the dissemination of
the virus throughout the body and the development of
clinical manifestations (Fig. 1B )30,35.
ZIKV transmission can be vector-borne or non-vector-borne1.
Vector-borne transmission occurs when the virus infects the
host through mosquito bites36. This explains the sylvatic
transmission cycle, where non-human primates and endemic
mosquitoes (enzootic vectors) are involved, as well as
human-mosquito-human transmission in urban and subur-
ban regions1,37. On the other hand, the mechanisms of
non-vectorial infection that has been described are sexual38,
vertical39, perinatal40, blood transfusion, and organ trans-
plantation41, as well as contact with body secretions such
as tears, saliva, urine, or sweat42.
Vertical, maternal-fetal transmission of Flaviviruses is
unusual. It has been proposed that these viruses follow
different pathways that vary according to gestational
age and the route of maternal infection (vectorial or
non-vectorial) to invade and replicate viral proteins in
fetal tissue43,44.
Pathophysiology
ZIKV has a strong tropism to ectodermal derivatives,
which confers greater dissemination potential with a
wide variety of clinical manifestations and specic alter-
ations according to the infected tissue35,45. It has been
reported that ZIKV presents neuronal tropism and
towards other organs, such as the liver, kidney, heart,
spleen, testicle, and ovary since viral RNA has been
found in these tissues30,46,47.
ZIKV tropism is mediated by type I and III interfer-
on-stimulated genes, which induce signaling for the pro-
duction of membrane proteins AXL and Tyro-3, members
of the receptor tyrosine kinase-like protein family, which
are expressed mainly in neuronal progenitor cells and
play an important role in embryonic developmental
homeostasis. In addition, the TIM1 glycoprotein, which
interacts with ZIKV, has been found in multiple target
organs, such as Hofbauer cells or placental macro-
phages, endothelium, and cytotrophoblast30,47.
Moreover, detection of ZIKV RNA in fetal tissues has
also been reported in the umbilical cord, placental cells
such as macrophages, amniotic uid, and brain, as well
as in tissues from spontaneous abortions of rst and
second-trimester human fetuses, mainly in placenta and
brain8,30,47. In vitro studies suggest that viral replication
occurs mainly in Hofbauer cells, trophoblast cells, and
fetal endothelium48-50.
Vertical transmission of ZIKV can develop through
the interaction of the virus in maternal blood or uterine
Table2. Functions of Zika virus proteins
Type Protein Function
Structural Protein C Forms the viral capsid
Protein E Enables membrane binding and
fusion with the host cell,
penetration and
hemagglutination during the
viral replication cycle
Protein
prM
Generates M protein, which
releases mature virion out of
the cell forming complexes
with E protein
Non‑structural NS1 Initiates the process of viral
RNA genome synthesis
NS2A Interacts with NS3 and NS5 for
viral packaging and replication
NS2B Interacts with NS3 for viral
packaging and replication
NS3 Harbors RNA protease and
helicase activity, essential for
viral replication and survival
NS4A Participates in the localization
of the replication complex to
the membrane
NS4B Assists NS3 protein
NS5 Participates in the inhibition of
the host innate immune system
and is a coadjuvant of the NS3
protein in the nuclear
localization of the virus
Adapted from Panwar28.

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I.E. Crisanto-López et al. Congenital Zika syndrome
broblasts with embryonic cells35,51. For this, two
hypotheses are considered: direct transfer or placental
mediated response on placental precursor tissue such
as trophoblast, chorioamniotic villi and membranes,
Hofbauer cells, umbilical cord endothelial cells, and
amniotic epithelial cells44,50-52. The direct transfer the-
ory stipulates that viral contact occurs within the rst
10weeks of gestation through the presence of ZIKV in
maternal blood or uterine broblasts, thus infecting
embryonic precursor cells of neuronal tissue due to its
neurotropism. On the other hand, the theory of placental
response can be considered complementary to the
pathophysiology since the inammatory response
caused by ZIKV infection produces a disruption of
placental signals that mediate neuronal development
and changes the prole of inammatory markers in fetal
organs, which eventually generates the clinical manifes-
tations depending on the specic tissue affected49,52-54.
According to the CDC, approximately 5% of pregnant
patients with maternal ZIKV infection either lose the
pregnancy or develop birth defects50,51. Gestational age
and host genetic variation are important determinants
of placental infection and immune system function35. In
addition, infection acquired during the rst trimester
increases the risk of developing CZS in the embryo51,55.
Statistically, infection in the rst two trimesters is asso-
ciated with severe alterations in target organs such as
the brain, eye, and male and female genital tract;
Protein E
Protein M
Protein C
Viral RNA
E protein-
mediated
ZIKV entry
ZIKV-
specific
receptor
Viroplasma
NS protein
binding
to ER
NS4A - ER
Viral RNA replication
NS1-NS3-MS5-NS4B
Endoplasmic
reticulum
Nucleus
Golgi apparatus
Viral RNA
packaging
vesicles
NS2A-NS2B
Structural
proteins
ZIKV
release
ZIKV
B
A
Figure1. Zika virus. A: structure. B: viral cycle.

8
Bol Med Hosp Infant Mex. 2023;80(1)
however, infection in any trimester of pregnancy is
associated with adverse fetal outcomes35,55-57.
During the 3rdweek of embryonic development, gas-
trulation and, thus, organogenesis begins. The external
epithelium of the body and the neural tube are formed
from the ectoderm. The external body epithelium gives
rise to organs and structures that are in contact with
the outside world (e.g., sensory epithelium of the ear,
nose, and eye, epidermis, skin, nails, mammary, sweat,
and sebaceous glands), anterior pituitary, and tooth
enamel. At the same time, from the neural tube, the
components of the nervous system are formed from the
neural plate (notochord-induced thickening of the ecto-
derm) and neural crest cells (NCC) (Fig.2)58,59.
NCCs undergo an epithelial-mesenchymal transition
for their active movement and migration into the meso-
derm50, directed by the expression of the bone morpho-
genetic protein, WNT signaling pathways, and by
broblast stimulating factor 8 expressed by the meso-
derm. In addition, they are regulated by the expression
of cell adhesion molecules and extracellular matrix mol-
ecules (bronectin, laminin, and typeIV collagen), lo-
podia, guidance molecules (neuropilin/semaphorin),
and by planar cell polarity. It should be noted that NCCs
can be differentiated by prior programming and by inter-
action with nearby tissues59. NCCs are divided into
three regions for their study: cranial, circumpharyngeal,
and truncal, each with specic derivatives according to
its region59. NCCs contribute to the formation of the
peripheral nervous system, meninges, melanocytes,
odontoblasts, medullary chromaffin cells, and a large
part of the connective tissues that form the cervical and
craniofacial territory, including bone, cartilage, and
muscle tissue60. This is why an agent with ectodermal
tropism can present diverse clinical manifestations61.
Clinical, embryonic, and fetal
manifestations of CZS
The clinical features of CZS are a consequence of
direct neurological involvement and intracranial volume
loss, causing structural, and functional alterations4,62,63.
Structural alterations include cranial morphology, cere-
bral and ocular anomalies, congenital contractures, and
mainly microcephaly (Fig. 3A-C)64, while functional
alterations are exclusively related to neurological
impairment55,65,66.
Chronic cerebral neuropathy in ZIKV-infected children
consists of intracranial calcications, typically subcortical
(Fig.4A and B), increased uid spaces (ventricular and
extra-axial) (Fig. 4C and D), cortical thinning with
abnormalities in the convolutions (polymicrogyria, pachy-
gyria, and agyria), hypoplasia or absence of the corpus
callosum, decreased myelin, and hypoplasia of the cer-
ebellum or cerebellar vermis67-69.
Calcications have also been identied in the basal
ganglia and brainstem. Ultrasound or magnetic
C
B
A
Figure3. Newborn with clinical features of microcephaly.
Female patient at 39weeks of gestation. Aand B: frontal
view. C: lateral view. Image obtained from Aviña‑Padilla et
al.64.
Epiblast
Ectoderm
External body epithelium Neural tube
Mammary glands,
sebaceous glands,
sweat glands, hair,
nails, proctodermal
epithelium,
auditory vesicle,
lens and cornea
Optic vesicle, epiphysis,
posterior pituitary,
cerebrum and
spinal cord
Neural crest cells
Figure2. Ectodermal germinal layer derivatives.

9
I.E. Crisanto-López et al. Congenital Zika syndrome
resonance imaging (MRI) studies can detect these
brain abnormalities during the prenatal period. In
cases of microcephaly, damage of the central nervous
system caused by ZIKV occurs by direct and indirect
cellular injury through various pathways such as apop-
tosis, regulation of the immune response, ubiquitina-
tion, and viral replication, mostly in neuronal progenitor
cells35,70. This apoptotic capacity may explain the
alterations in the embryonic neurodevelopment of
infected products. In addition, experiments have been
reported in animal models, where infection in postna-
tal products causes dysfunction of cell death path-
ways, decreased proliferation of stem cells in the
periventricular zone, and disruption of corticospinal
pyramidal neurons71,72. These are not the only factors
contributing to microcephaly caused by ZIKV; NCCs
are also affected by this virus. Consequently, they
produce pro-inammatory cytokines that induce apop-
tosis via the paracrine pathway affecting neuronal pro-
genitor cells35.
Neurological alterations caused by ZIKV infection
include hypertonia, hypotonia, spasticity, hyperreexia,
severe irritability, and seizures. Some patients with con-
rmed or probable infection present fetal disruption
sequence phenotype, characterized by severe micro-
cephaly, marked craniofacial disproportion, occipital
bone prominence, altered hair implantation, short neck,
redundant nuchal and cranial folds, retrognathia, con-
tractures, and multiple arthrogryposes73,74.
In the eyes, viral RNA has been detected in the cor-
nea, optic nerve, and neurosensory retina. The most
frequent ocular structural anomalies are, in particular,
microphthalmia, coloboma, congenital cataracts, and
intraocular calcications. Likewise, cases of chorioreti-
nal atrophy and retinitis pigmentosa have been reported,
generally affecting the macular region and producing
atrophy of the optic nerve75.
In the male reproductive tract, the infection damages
spermatogonia and Sertoli cells, destroys testicular
architecture, decreases sperm motility, and thus
reduces fertility76. In parallel, in the female genital tract,
viral RNA has been reported in the cervical mucosa up
to 11days after the onset of symptoms. In vitro studies
showed that uterine broblasts have increased suscep-
tibility to ZIKV, contributing to fetal developmental
damage35,77.
On the other hand, congenital contractures of one or
multiple joints (arthrogryposis multiplex congenita)
have been described in fetuses and newborns with
congenital ZIKV infection. The clinical picture of con-
genital contractures varies according to proximal or
distal location, laterality, upper or lower limb, and sever-
ity, as reected by neurological damage78,79.
Neurogenic factors affecting the corticospinal tract
and motor neurons or their interactions may cause fetal
motor abnormalities, resulting in decreased movements
and contractures. However, the specic mechanism
causing contractures in prenatal ZIKV infection is not
yet fully understood80.
To date, the means of non-vectorial transmission and
the pathophysiology at the molecular level of this con-
dition are still under investigation.
Diagnosis
Due to the severe effects caused by ZIKV infection
on embryonic and fetal development, it is necessary to
identify risk factors and make a timely diagnosis. As
has been described, CZS can present diverse clinical
manifestations, both mild and severe; in addition, the
clinical data presented are nonspecic since different
infections can also cause them during pregnancy81.
Therefore, it is important to detect pregnant patients
D
C
B
A
Figure4. CT scan of newborn with severe microcephaly.
A: profound craniofacial disproportion, corpus callosum
(short white arrow), brainstem (long white arrow) and
cerebellar hypoplasia (short black arrow), enlarged
cisterna magna (long black arrow). B: calcifications in
frontal lobe. C: severe ventriculomegaly. D: increased
thickness of pachymeninges. Image obtained from de
Fatima Vasco Aragao et al.68.

10
Bol Med Hosp Infant Mex. 2023;80(1)
with probable ZIKV infection through adequate prenatal
screening, where all pregnant women should be eval-
uated to identify possible risk factors82.
Risk factors for ZIKV exposure include81-84:
–Living in or having visited areas with active ZIKV trans-
mission in the past 15days or during pregnancy.
–Having had unprotected sex in the 2 weeks before
conception with a partner who has traveled or lived
in areas with active virus transmission in the previous
6months, regardless of whether or not symptomatol-
ogy was present.
The clinical presentation of CZS is generally charac-
terized by disruption in brain development, both embry-
onically and at the fetal level20,85, characterized by
direct neurological disturbance followed by the collapse
of the fetal cranial vault due to decreased intracranial
hydrostatic pressure4,62,63.
For its study and diagnosis, PAHO has typied CZS
under the following criteria86:
A case of congenital syndrome suspected to be
associated with ZIKV infection is determined when the
live newborn presents:
–Microcephaly, whose occipitofrontal head circumfer-
ence measurement is below the third percentile ac-
cording to standard growth charts for age, sex, and
gestational age at 24h after birth.
–Maternal history of residence or travel to an area with
circulation or suspected circulation of ZIKV.
–Unprotected sex with a partner with a history of res-
idence or travel to an area with ZIKV circulation or
suspected ZIKV circulation.
A case of congenital syndrome probably associated
with ZIKV infection is determined when the live new-
born meets the criteria for a case of congenital syn-
drome suspected to be associated with ZIKV infection
and with any of the following features:
–Intracranial morphological alterations diagnosed by
any imaging method, excluding other known possible
causes.
–Maternal history of having presented with exanthema
during pregnancy.
A case of congenital syndrome conrmed to be asso-
ciated with ZIKV infection:
–When the live newborn of any gestational age
meets the criteria for a case of congenital syndrome
suspected of being associated with ZIKV infection
and in whom ZIKV infection has been laboratory
conrmed, regardless of the detection of other
agents.
Infection by vertical transmission can occur in any
trimester of pregnancy, regardless of whether the
mother has symptoms or not20,55,59,60. However, not all
products exposed to ZIKV become affected. It is esti-
mated that 70-80% of exposed products do not present
alterations suggestive of ZIKV infection. Of the 20-30%
who become infected, only 5-14% develop CZS. On the
other hand, about 4-7% culminate in fetal loss; the rest
are asymptomatic20.
The general malformations associated with CZS
are81:
–Severe microcephaly, where the skull has partially
collapsed.
–Decreased brain tissue with calcications in the sub-
cortical region.
–Damage of the fundus, manifesting with macular
scarring and focal retinal pigmentary staining.
–Congenital contractures such as clubfoot (talipes) or
arthrogryposis.
–Congenital hypertonia limiting body movement short-
ly after birth.
It should be noted that microcephaly caused by ZIKV
is diagnosed under the following parameters81:
Dened dongenital microcephaly:
–For live births:
• Occipitofrontal circumference at birth less than the
3rdpercentile for gestational age and sex within the
rst 2weeks of life.
–For stillbirths and elective terminations
• Occipitofrontalcircumferenceatbirthlessthanthe
3rdpercentile for gestational age and sex.
Possible congenital microcephaly
–For live births
• Occipitofrontalcircumferencelessthanthe3rdper-
centile for age and sex after 6weeks of age.
–For all pregnancy outcomes
• Microcephaly diagnosedorsuspectedbyprenatal
ultrasound in the absence of available postnatal
occipitofrontal circumference measurements.
The imaging methods for CZS diagnosis are ultraso-
nography (USG), computed tomography (CT), and
MRI87. It is important to remember that during preg-
nancy, ultrasounds should be performed every trimes-
ter for fetal and maternal risk screening during prenatal
control visits. Likewise, during the intrauterine stage, it
is also advisable to use USG and MRI; while in the
extrauterine stage, CT can be performed82,88.
Cranial alterations such as microcephaly and intracra-
nial calcications can be identied mainly at the end of
the second and beginning of the third trimester89. On the
other hand, images taken by CT or MRI can identify some
of the ndings that have been described in patients with
CZS, such as intracranial calcications, ventriculomegaly,

11
I.E. Crisanto-López et al. Congenital Zika syndrome
increased extra-axial uid, polymicrogyria (alterations of
neuronal migrations resulting in excessive cortical folds
and shallow sulci), reduction of brain parenchymal vol-
ume, cortical atrophy or malformation, hypoplasia of the
cerebellum or cerebellar vermis, delayed myelination, and
hypoplasia of the corpus callosum40,89-91.
In addition, laboratory diagnosis of CZS should be
made on clinical suspicion and identication of risk
factors by molecular testing to conrm or rule out the
presence of ZIKV, such as real-time polymerase chain
reaction or time-dependent neutralization of antibodies
(NNT), with blood samples from both the newborn and
the mother, or embryonic annexes such as the umbili-
cal cord or placenta, to prevent possible cases of
CZS92,93. Detection of immunoglobulin (Ig)M antibodies
is possible by enzyme-linked immunoadsorbent assay
and immunouorescence in cerebrospinal uid sam-
ples or by amniocentesis73,86,93. IgM antibodies can be
detected in serum from the 5th or 6th day after symp-
toms onset, and a positive serology requires a positive
NNT test to conrm infection. For this purpose, it is
important to strictly follow-up prenatal and postnatal
control, both for the mother and the newborn40,75.
Laboratory criteria for ZIKV infection in pregnant
patients are as follows. For conrmed cases, virus isola-
tion in a clinical specimen (blood/urine), nucleic acid
detection in a clinical specimen (blood/urine), and detec-
tion of NNT in IgM-positive specimens. For probable
cases, the presence of IgM antibodies, not conrmed by
NNT in a serum sample, seroconversion of virus-specic
IgG antibodies, or a four-fold increase in titer between
samples taken in the acute and convalescent phase, the
rst serum is collected at the onset of the disease, and
the second 10-14 days later. Furthermore, the detection
of NNT in samples with negative IgM and positive IgG
markers73. When congenital infection is suspected, it is
advisable to perform laboratory tests to determine the
presence of cytomegalovirus, herpes simplex, rubella,
human immunodeciency virus, toxoplasmosis, and syph-
ilis infection to rule out other possible etiologies54,69.
Treatment
Given the severe alterations caused by CZS, there is
no specic treatment, and therapeutic measures are
symptomatic, aimed at maintaining an adequate hydric
status for the patient, as well as the use of analgesics
and antipyretics. At present, some specic antiviral
treatments and the development of anti-Zika vaccines
are under study20,35,73,94.
Patients with SCZ require constant monitoring, mul-
tidisciplinary care, referral to early intervention and
stimulation centers, and family counseling20. Therefore,
preventive measures are of major importance to avoid
cases of CZS.
Preventive measures
According to PAHO and WHO, the best way to prevent
the infection of communicable diseases is to control their
vectors. Therefore, it is recommended to increase efforts
to implement effective strategies to reduce vector den-
sity, mainly of the transmitting mosquito, which is widely
distributed in the American continent, and the danger of
exposure increases due to the emerging risk of popula-
tion movement and migration95.
In countries without local cases of ZIKV infection, it
is recommended that patients with suspected ZIKV
infection be tested for the virus to identify the circulating
viral strains, the appropriate characterization of the out-
break, and the implementation of an adequate response.
In countries with local cases of ZIKV infection, it is
recommended to monitor the geographic spread of the
virus to delimit the affected area, assess the clinical
severity and public health impact, identify risk factors
associated with ZIKV infection, and identify circulating
ZIKV lineages. Any changes detected through surveil-
lance should be promptly reported to the national pre-
vention and control authorities to ensure that appropriate
action is taken on time73,95,96. It is also necessary to
take personal preventive measures, including wearing
appropriate clothing (cotton and neutral colors) that
covers most of the body (long-sleeved shirts, pants,
socks, or caps, especially during peak mosquito activity
hours). It is recommended to use mosquito nets on
windows, doors, and at night, on the child’s bed or crib.
Furthermore, use mosquito repellents containing dieth-
yltoluamide, picaridin, or icaridin according to the prod-
uct manufacturer’s instructions. In the house, look for
and destroy possible sources of mosquito breeding
sites by avoiding accumulations of stagnant water. For
couples who wish to conceive, and either partner has
traveled to high-risk areas, it is recommended that
pregnancy be postponed for at least 8weeks after the
onset of symptoms or last possible exposure to the
virus for women (symptomatic or not) or at least
6months after the onset of symptoms or last possible
exposure to the virus for men (symptomatic or not).
Sexual partners of pregnant women returning from
areas with local ZIKV transmission should maintain
barrier-protected sex throughout pregnancy95,96.

12
Bol Med Hosp Infant Mex. 2023;80(1)
In conclusion, CZS is a pathological entity of wide
distribution and easy transmission that can produce
severe affectations. Its clinical presentation varies from
asymptomatic to severe alterations that compromise the
quality of life and even the course of life. The main neo-
natal clinical manifestations are microcephaly, ventricu-
lomegaly, intracranial calcications, ocular alterations,
and congenital contractures. Its diagnosis is complex
due to the variety of its clinical manifestations and its
unspecicity; in addition, there is no specic treatment.
As health personnel, it is important to be constantly
updated on this subject to identify risk factors, make a
timely diagnosis and thus avoid both the effects during
embryological development and the spread of this virus
to more people in the population. Although there is no
treatment or vaccine, personal prevention measures
are straightforward and inexpensive, so it is essential
to know them and promote them to avoid further com-
plications. It is also important to continue with lines of
research to better understand the pathogenic pathways
through which it acts, optimize the diagnostic protocol,
and produce specic therapeutic measures.
Ethical disclosures
Protection of human and animal subjects. The
authors declare that no experiments were performed
on humans or animals for this study.
Confidentiality of data. The authors declare that
they have followed the protocols of their work center on
the publication of patient data.
Right to privacy and informed consent. The
authors have obtained the written informed consent of
the patients or subjects mentioned in the article. The
corresponding author has this document.
Conflicts of interest
The authors declare that they have no conicts of
interest.
Funding
No funding.
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