Volume 2 | Issue 1 | Year 2023

Congenital Zika Virus Infections

Yahya Ethawi1, Gangajal Kasniya2, Nibras Al Baiti3, Rehab Mohammed4, FatimaElzahara Taha Mohammad5, Roya Arif Huseynova6

1Department of Neonatology, Saudi German Hospital Ajman (SGHA), Sharjah, United Arab Emirates

2Department of Neonatal–Perinatal Medicine, Cohen Children’s Medical Center, New Hyde Park, New York, United States of America

3Department of Obstetrics, Saudi German Hospital at Sharjah (SGHS), Sharjah, United Arab Emirates

4Department of Pediatrics, Al Batool Teaching Hospital, Mosul, Iraq

5Department of Pediatrics, SGHA, Ajman, United Arab Emirates

6Neonatal Intensive Care Unit (NICU), King Saud Medical City, Riyadh, Saudi Arabia

Corresponding Author: Yahya Ethawi, Department of Neonatology, Saudi German Hospital Ajman (SGHA), Sharjah, United Arab Emirates, Phone: +971 505448203, e-mail:

How to cite this article: Ethawi Y, Kasniya G, Al Baiti N, et al. Congenital Zika Virus Infections. Newborn 2023;2(1):91–101.

Source of support: Nil

Conflict of interest: Dr. Yahya Ethawi is associated as the Editorial Board Member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this Editorial Board Member and his research group.

Received on: 28 February 2023; Accepted on: 22 March 2023; Published on: 06 April 2023


Zika virus (ZIKV) is an arthropod-borne flavivirus transmitted through bites of the Aedes mosquitoes. Infected mothers can vertically transmit ZIKV to their fetuses, particularly during the first and second trimesters. Infections beginning during early gestation can cause congenital Zika virus syndrome (CZS), which may be marked by arrested development and/or altered healing in the nervous system. There can be microcephaly, craniosynostosis, intracranial calcifications, ventriculomegaly, low brain volume and/or cortical atrophy, and hypoplasia/altered myelination in the corpus callosum, cerebellum, and brainstem. There may also be altered development with polymicrogyria, pachygyria, and lissencephaly. Clinically, infants with CZS may show facial dysmorphism, pulmonary hypoplasia, altered growth and development, hypertonia, hyperreflexia, limb contractures, and arthrogryposis multiplex. Perinatal infections can present with irritability, seizures, eye involvement, and sensorineural hearing loss (SNHL). Congenital zika virus syn and perinatal infections contrast with those acquired after birth, which usually have a relatively milder course. Overall, the mortality rate can reach 4–6%. Laboratory evaluation can include polymerase chain reactions on serum, cerebrospinal fluid, and urine; testing for immunoglobulin M (IgM); and plaque reduction neutralization tests (PRNTs) to confirm the specificity of these Zika virus IgM (ZIKV IgM) antibodies. Unfortunately, no specific treatment is available; most measures are largely supportive.

Keywords: Congenital Zika syndrome, Newborn, Real-time reverse transcription-polymerase chain reaction, Magnetic resonance imaging, Zika virus infection.


Zika virus (ZIKV) was first isolated from a sentinel primate in Uganda in 1947.1 It is a mosquito-borne virus named after the Zika Forest in Central Africa.2,3 It circulated unnoticed in some regions in Africa and Southeast Asia until 2007, until an outbreak was recorded in the Yap Island in Micronesia.4,5 The virus has since spread to parts of Central and South America and the Caribbean.68 A major epidemic was seen in Brazil in 2015.9,10 The incidence has gradually risen with new cases now having been reported from nearly 80 countries worldwide.1114

The term congenital zika virus syndrome (CZS) has been used to describe the complicated clinical course seen in neonates born to mothers infected with ZIKV.1517 Several prospective cohort studies have shown that fetal ZIKV exposure in utero is associated with adverse birth outcomes and neurologic sequelae.1820 Unlike postnatal ZIKV infections after birth and in adults, congenital infections tend to be more severe and may be associated with neurological and multi-system complications.13,21 In this article, we have focused on these vertically transmitted ZIKV infections.22

Zika Virus: Classification and Structure

Zika virus belongs to the Flaviviridae family of positive-strand RNA viruses that includes human pathogens such as the mosquito-transmitted dengue virus, West Nile virus, Japanese encephalitis virus, yellow fever virus, and the tick-borne encephalitic virus.2331 Flaviviruses are enveloped viruses containing an RNA genome of about 11 kilobase (kB).32 There are multiple copies of a capsid protein, which is surrounded by an icosahedral shell consisting of 180 copies each of the envelope glycoprotein (about 500 amino acids) and a membrane protein (about 75 amino acids its precursor of about 165 amino acids); both are anchored in a lipid membrane.3236 There are seven non-structural proteins that are needed for replication, assembly, and for antagonizing the host innate immune responses.3740

Flaviviruses evolve through three stages, including immature, mature, and fusogenic.41,42 These are non-infectious, infectious, and host membrane–binding states, respectively.39 The immature “spiky” immature particle is assembled in the ER and is non-infectious.43 It matures through conformational changes of the surface glycoproteins into a “smooth” particle in the low-pH environment of the trans-Golgi network.44 The fusogenic stage is marked by an endosomal fusion loop seen in conditions with acidic pH.45

In this group of viruses, ZIKV specifically contains a typical flavivirus genome that is 10.8 kB long (Fig. 1).44 The RNA is translated into a single polyprotein (3,423 amino acids) that is processed into the 3 above-mentioned structural proteins.46 The capsid contains four α helices with a long pre-α1 loop and forms dimers; the pre-α1 loop contributes to the tighter association of dimeric assembly.35,36,47,48 The membrane protein contains two loops that anchor it to the membrane.43 Finally, the envelope protein is comprised of four domains; the stem-transmembrane domain anchors the protein into the membrane.39 The seven non-structural proteins are labeled NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. Interestingly, some of these proteins regulate viral replication.49 The structural proteins form the virus particle, whereas the non-structural proteins assist in the replication and packaging of the genome.50 The generation of the 10 individual proteins from the polyprotein is regulated by viral and host proteases, and the efficiency of furin, a host protease that cleaves the viral targets.51,52

Figs 1A and B: (A) Schematic illustration of ZIKV: Zika virions are enveloped, 18–45 nanometer icosahedral structures. The genome is a positive strand RNA enclosed in a capsid and surrounded by a membrane. The RNA contains 10,794 nucleotides encoding 3,419 amino acids. (B) The ZIKV genome. The 10.8 kB long genome is translated into a single polyprotein, which is then processed into a capsid protein (C), an envelope glycoprotein (E) and membrane protein (proM, processed to M), and 7 non-structural proteins that are labeled NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. UTR = Untranslated region; prM = uncleaved pro-membrane protein; C = capsule; E = envelope; NS = non-structural protein. The mature ZIKV particle is about 50-nm in diameter. It has 180 copies of the E and M proteins embedded in the membrane. The E protein is comprised of four domains: A stem-transmembrane domain pair and three ectodomains I, II, and III seen outside of the membrane. The E protein exists as a dimer and predominates on the surface of the virion with the smaller M protein residing underneath. The M protein has a smaller extracellular region and a stem-transmembrane domain. Three E proteins dimers lie parallel to one another in a raft configuration, with the virion having a total of 30 rafts. The non-structural proteins assist in replication and packaging of the genome.


ZIKV is transmitted to humans primarily through the bites of infected Aedes mosquitoes, particularly those of the species Ae. aegypti and Ae. albopictus.53 These mosquitoes live near human habitations and frequently get infected with viruses such as Zika, chikungunya, and dengue after biting infected persons who are viremic such as during the first week of infection.54 These mosquitoes lay eggs in standing water such as near the edges of lakes and ponds, in plants in swamps and marshes, or in containers that hold water such as buckets, bowls, and animal dishes.55 These mosquitoes bite humans and can transfer the viruses to other hosts.56

A pregnant woman can pass ZIKV to her fetus during pregnancy or the perinatal period.57 Zika virus has also been found in mother’s own milk, although viral transmission through breast milk has not been confirmed yet.58 Flavivirus nucleic acid has been detected in breast milk.59 However, we do not know the long-term effects of postnatal ZIKV transmission.60 The benefits of breastfeeding may outweigh the risk of transmission through breast milk, and the Centers for Disease Control and Prevention (CDC) continue to encourage mothers to breastfeed even if they lived/traveled to endemic areas or were infected with ZIKV.61

Zika virus can be sexually transmitted from an infected person to his or her partners.62 Many individuals with minimal symptoms can be infectious; studies suggest that ZIKV can be passed from an infected persons before the onset of symptoms, during acute illness, or after apparent clinical recovery.63 Studies are on to determine the duration for which ZIKV remains detectable in semen and vaginal fluid of infected individuals, and their infectivity.64 The virus may remain detectable in semen longer than in other body fluids such as vaginal fluids, urine, blood, conjunctival fluid, and amniotic fluid.65,66

Reports from Brazil and other countries have documented the presence of ZIKV in blood donated for transfusions.67 During the French Polynesian outbreak, 2.8% of blood donors tested positive for ZIKV.68 There are some reports of laboratory-acquired ZV infections, although the route of transmission could not always be established.69 There is a need to investigate these reports because ZIKV diagnostic testing and laboratory research have expanded with increased risk of occupational exposure to laboratory workers and biomedical researchers.70 The emergency committee of the World Health Organization (WHO) announced ZIKV disease as a Public Health Emergency of International Concern in 2016 and triggered the exploration of global involvement to define the pathophysiology and deal with the related clinical challenges.71


The mechanisms of the ZIKV passage across the placental barrier, the association between viremia and the development of CZS, and the exact timing of placental and fetal infection with maternal viremia are still not clear.72 ZIKV can infect placental macrophages, trophoblasts, and endothelial cells, and then enter the fetus from these cells.73 In infected fetuses, ZIKV has been isolated from the brain and cerebrospinal fluid.21 However, the impact of placental infection in defining the syndrome’s severity has not been confirmed yet.74

ZIKV infections of the fetal brain can damage the neuronal progenitor cells and interrupt neuronal proliferation, migration, and differentiation.75 These events may slow or interrupt brain growth beginning at 20 weeks of gestation.76,77 The risk of neurodevelopmental abnormalities in infected fetuses is the highest when maternal infection appears during the first and second trimesters of pregnancy because it is a crucial period for brain development.78 Interestingly, some neonates who were exposed to ZIKV in utero did not show obvious abnormalities at birth but developed impairments over time.79,80 In these infants, ZV replication may have continued after birth and interrupted brain growth.79 Clearly, ZIKV-exposed fetuses need continued, comprehensive follow-up after birth.81


ZIKV is a neurotropic virus that specifically attacks neural progenitor cells.82,83 Electron micrographs show ZIKV as dense particles in the damaged endoplasmic reticulum (ER) in these cells. This ER stress/unfolded protein response not only suppresses the proliferation of cortical progenitor cells but also damages mature neurons in the cerebral cortex.83,84 Specific groups of enveloped structures with a bright interior resembling the residue of replication complex also support ZIKV replication in the neonatal brain.39

Zika infections in the developing brain may manifest with diffuse arachnoiditis with ependymitis and vasculitis.85 Some foci show meningoencephalitis, ventriculomegaly or an ex vacuo hydrocephalus, microcephaly with lissencephaly, and cerebellar hypoplasia.86 An additional spectrum of parenchymal lesions was observed involving the whole hemispheric wall namely the cortical plate (CP), the intermediate, and the ventricular zones. The CP lesions consisted in a loss of lamination with radial glia disruption, focal polymicrogyria, neuronal loss, chromatin fragmentation with numerous apoptotic residues and mineralization.86 The loss of lamination can disrupt radial glia and cause a diffuse loss of neurons.

Necrotic lesions can be seen in the subcortical region in the vicinity of damaged vessels.86 The loss of cortical neurons has been linked with ZIKV-associated microcephaly.87 Several neurobiological studies have shown increased cell death and the impaired cell cycle leading to a decreased neural progenitor cell proliferation, causing a decrease in the number of cortical neurons.88 In addition to ER stress, ZIKV infection can cause chromatin change and necroptosis.89 Viral particles have been observed in basal/apical progenitor cells, neurons in the cortical plate, and in the ventricular and subventricular zones.90 The loss of callosal fibers and longitudinal tracts has been identified as a cause of the cerebral atrophy and the ventricular enlargement.91 The disruption of the hypothalamic and pituitary axis can cause adrenal gland atrophy.92

Immunohistochemical studies may show T-lymphocytic and histiocytic meningitis with abundant cerebral astroglial and macrophagic reactions.85 Vasculitis is marked by the presence of swollen endothelial cells surrounded by active microglia and astrocytes.93,94 In the cerebellum, the width of the external and the internal granular layers was reduced.85 The neurons were shrunken and contained fragmented chromatin (karyorrhexis).95,96 Macrophages and numerous hypertrophic astrocytes were present.96 In the spinal cord, the astrocytic and macrophagic reaction was mild and neurons were spared.83 The longitudinal tracts were missing. Glial fibrillary acidic protein-reactive antibody confirmed the astroglial nature of the gliosis seen close to the necrotic regions in the subventricular and in the intermediate zones.21

In situ hybridization shows ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate.77 The neuronal precursor cell is the main target for ZIKV leading to cell death, although, neuronal cells in all stages of maturity can be affected.82 These changes can explain the microcephaly and poor cortical gyration.97 Moreover, viral cerebritis can affect cerebral embryogenesis and result in microcephaly or other central nervous system abnormalities.85,98

There may be inflammatory changes in other organs. The placenta may contain a Hofbauer cells hyperplasia with signs of inflammation.99 Truncal vessels may show fibromuscular hypertrophy causing a narrowing of the lumen.85 Some cases may show features of acute chorioamnionitis, villitis, and funisitis.100 Some studies have shown an interstitial lymphocytic infiltrate in the testes.101

Clinical Manifestations

The full CZS spectrum is evolving with the recognition of the following subtle manifestations in growing infants:

  • Fetal growth restriction.102107

  • Congenital anomalies in 7–40% of infants.108111 Central nervous system findings include large ventricles, microcephaly, and intracranial calcifications.112 Some infants show craniosynostosis, low brain volume and/or cortical atrophy (Fig. 2), and hypoplasia/altered myelination in the corpus callosum, cerebellum, and brainstem. There may also be altered structural development with polymicrogyria, pachygyria, and lissencephaly. Clinically, infants with CZS may show facial dysmorphism, pulmonary hypoplasia, altered growth and development, hypertonia, hyperreflexia, limb contractures, and arthrogryposis multiplex.

  • Perinatal infections can present with irritability, seizures, eye involvement, and sensorineural hearing loss (SNHL). Congenital Zika syndrome and perinatal infections contrast with those acquired after birth, which usually have a relatively milder course.

  • Fetal/perinatal death.113

Fig. 2: Axial CT image of an infant with congenital ZIKV infection and severe microcephaly shows cerebral atrophy with ventriculomegaly, prominent cerebrospinal fluid space, and extensive, punctate cortico–subcortical calcifications.

There are five signs that have recorded frequently in infants with CZS as follows:

  • Decreased brain tissue with subcortical calcifications.

  • Microcephaly.

  • Hypertonia with limitations of body movement seen shortly after birth.

  • Congenital joint contractures such as arthrogryposis and clubfoot.

  • Eye lesions, such as focal retinal pigmentary mottling and macular scarring.

The following findings are relatively more specific to CZS:114 (a) Partially collapsed skull with severe microcephaly, (b) subcortical calcifications with thin cerebral cortices, (c) focal pigmentary retinal mottling with macular scarring, (d) congenital contractures and arthrogryposis, and (e) severe early hypertonia.115


The incidence of microcephaly has varied across studies. In some small cohorts, up to 90% of cases of CZV had microcephaly, and most cases have severe congenital microcephaly.98,116 Other studies have shown lower incidence figures, with only 5–9% of infants with CZS having a small head circumference.117 In a large cohort, Cauchemez et al.103 estimated the frequency of microcephaly to be about 95 per 10,000 women infected during the first trimester. Severe microcephaly has been noted in 7–9% of all infants with CZS.100,108,113,118123 About 10% had moderate microcephaly.106

Microcephaly has been traditionally defined as an occipital head circumference (OHC; measured between occipital protuberance and glabella) that is 2 standard deviations (SDs) less than the average for gestational age (GA) or corrected GA. Severe microcephaly is defined as an OHC below 3 SDs.124 It can be a primary abnormality seen at birth or a secondary failure of head growth that develops over time.121,125 Proportionate microcephaly is a restriction of head circumference similar to that of length and weight. Infants with disproportionate microcephaly have a restricted head circumference but a normal weight and length.126

Infants with CZS frequently show disproportionate craniofacial dimensions where the face appears larger compared to a small head.127 Up to 78% of infants with CZV infections develop craniosynostosis;107,114 many show cutis gyrata where the continuously growing redundant scalp tissue begins to show folds over the cranium that is not growing any further.115 A CZS-associated microcephaly may reflect a less-than-normal number of gray matter neurons with reduced brain volume. Microcephaly is usually seen when ZV infections occur early in pregnancy; however, proportionate microcephaly has been observed in the offspring of women infected as late as the third trimester of pregnancy.128,129 In rare instances, microcephaly has been noted to resolve over time.129

Infants with CZV-related microcephaly frequently have seizures, cerebral palsy, and neurodevelopmental abnormalities. Many infants have abnormal facies, thin cerebral cortex on cranial imaging, macular scarring, focal pigmentary retinal changes, SNHL, irritability, hypertonia, hyperreflexia, and congenital contractures and talipes equinovarus due to decreased movements in utero.97,130 In one cohort, 6% of infants had congenital anomalies, and 9% had neurodevelopmental abnormalities such as developmental delay, hearing loss, and seizures.103 Neuroimaging showed major structural lesions in 42% and minor abnormalities in 24%. The physical (neurological) examination was abnormal in 21%. Nine percent were small-for-gestational age (SGA). Eye abnormalities were recorded in 7%, dysphagia in 3%, hearing defects in 3%, clinically evident or subclinical seizures (abnormal electroencephalogram) in 3%, and minor abnormalities in 10%.100

Ocular Manifestations

About 25% of infants with CZS showed eye abnormalities, which was considerably higher than the 6–7% incidence in the general population.131,132 These findings included macular abnormalities; focal pigmentary retinal changes; chorioretinal atrophy, and optic nerve abnormalities such as optic nerve hypoplasia, increased cup-disk ratio, and pallor.133136 Other changes included pigmentary clumping, coloboma, subretinal hemorrhages, vascular tortuosity, and abnormal retinal vessels with focal vascular dilation.137140 Iris colobomas, microcornea, microphthalmia, lens subluxation, cataracts, intraocular calcification, congenital glaucoma, strabismus, and nystagmus were also seen in some infants.141145 The eye findings in CZS were not progressive.132 Cortical visual impairment was the most likely cause of the loss of vision in infants with CZS.146,147 Major visual impairment in CZS was seen in 30%. However, the rate of visual impairment was as high as 84% when the associated eye findings were included.148

Other Abnormalities

Sensorineural hearing loss is seen in 7–12%.104 Arthrogryposis and club foot have been reported and are likely neurogenic in origin due to fixed posture in utero.149 Other clinical signs of CZS include hypertonia, hyperreflexia, irritability, feeding difficulties, and dysphagia.150 Seizures may occur due to underlying brain malformations, but may also be present in children without apparent CNS abnormalities with a median age of onset of a seizure is 4 months.106,151 The seizures are usually refractory with poor initial control with medical therapy. Notably, 30–40% of infants with CZS are SGA.107,130 Congenital heart disease (CHD) occurs in 10–15% and is mostly non-severe, such as secundum atrial septal defect (ASD), patent ductus arteriosus (PDA), and small muscular or peri-membranous ventricular septal defect (VSD) and few had hemodynamically significant CHD defect such as large membranous VSD.152,153

Perinatal Infections

Infants infected around the time of birth develop acute encephalopathy and can present with irritability, seizures, eye involvement, and SNHL.

Postnatal Infections

Most patients remain asymptomatic. A small minority develops a mild course of fever, rash, and conjunctivitis.58,154,155


Imaging can detect neurological abnormalities such as intracranial calcifications, ventriculomegaly, low brain volume, delayed myelination, polymicrogyria, pachygyria, lissencephaly, corpus callosum, brainstem, cerebellar thinning or hypoplasia, large cisterna magna, and increased extra-axial fluid spaces.156,157

Intracranial calcifications due to ZIKV are seen the most frequently at the junction of the cortical and subcortical white matter. Notably, these lesions differ from the punctate lesions caused by cytomegalovirus. However, calcification may occur in the periventricular region, basal ganglia, thalamus, brainstem, and cerebellum.158 These calcifications may diminish in number, size, or density with age in most children,159 although these changes do not correlate with clinical improvement as most patients; these patients may still develop severe neurological sequelae. Notably, 40% of infants with hydrocephalus may require a ventriculoperitoneal shunt. Cranial ultrasound is an important screening tool but it often needs to be followed up with magnetic resonance imaging (MRI) for detailed evaluation. CT scans can detect intracranial calcifications while MRI is better for structural brain disease. A negative sonographic examination in infants who have seizures, microcephaly, and tone abnormalities should be followed by a more extensive neurological evaluation by specialists and a specific imaging evaluation.


A detailed evaluation as detailed in the following list is needed for infants with ZIKV infections confirmed by maternal laboratory test and clinical evidence of CZI such as microcephaly and/or other congenital anomalies:160

  • Physical examination including anthropometric measurements (head circumference, length, and weight), neurologic abnormalities, and dysmorphic findings assessment.

  • Laboratory testing, including complete blood counts, and a metabolic panel with liver function tests.

  • Head ultrasound.

  • Hearing test using auditory brainstem response to assess hearing.

  • Eye examination by an experienced ophthalmologist before or shortly after discharge from the hospital.

  • Other specialties consultation (a) neurologist; (b) infectious disease specialist; (c) clinical geneticist; (d) early intervention and developmental specialists; and (v) family and supportive services.

  • Other optional consultations (a) orthopedist, (b) physiatrist, (c) physical and/or occupational therapists, (d) lactation specialist, (e) nutritionist; (f) gastroenterologist; (g) speech or occupational therapist; (h) endocrinologist for evaluation; (i) pulmonologist; (j) otolaryngologist; and (k) cardiologist.

The WHO and CDC define microcephaly as occipitofrontal circumference (OFC) above 2 SDs below the mean or below the third percentile for gender, age, and GA at birth.124,161,162 Severe microcephaly is a HC below 3 SDs below the mean.161 Both CDC and WHO recommend detailed clinical assessments before making a diagnosis of microcephaly to decide the plans for follow-up.124

Laboratory Evaluation

The following infants should be tested:160

  • The mother has evidence of ZIKV infections during pregnancy.

  • There are clinical or neuroimaging findings suggestive of CZS with maternal or paternal possible exposure, regardless of maternal ZIKV laboratory status.

The postnatal laboratory tests include the following:160,163

  • Serum and or urine for ZIKV RNA using real-time reverse transcriptase-polymerase chain reaction (rRT-PCR).

  • Serum Zika virus immunoglobulin M (IgM) using enzyme-linked immunosorbent assay (ELISA).

  • Cerebrospinal fluid (CSF; if available) for ZV RNA by rRT-PCR and ZIKV IgM.160,163 Early samples can distinguish between congenital, perinatal, and postnatal infection. Cord blood should not be used as it may yield false-positive results.160

  • Plaque reduction neutralization test (PRNT) detects specific neutralizing antibodies of the Zika and dengue viruses which is not available for routine use. It can confirm the specificity of IgM antibodies against the ZV, which can rule out a false-positive IgM test. For a positive or presumptive positive or possible positive or equivocal result without PRNT of the mother’s sample, a ZV PRNT on the infant’s initial sample is of great help. If the neonatal PRNT is initially positive, a repeat PRNT test should be done after the age of 18 months to differentiate true initial fetal infection from maternal passive transfer of antibodies, at which time maternally acquired antibodies will have waned.

Maternal serum should be checked for ZIKV IgM and its neutralizing antibodies. To distinguish from other arboviruses, the infants should be tested for dengue virus IgM and its neutralizing antibodies. The interpretation of these results is complex because of the cross-reaction between Zika and dengue antibodies. Neutralization assays can confirm or exclude the result. Histopathologic assessment of the placenta and umbilical cord can add more information.

Interpretation and Diagnosis

Confirmed diagnosis

In the first few days of life, ZIKV RNA present in the serum, urine, or CSF are collected, regardless of IgM antibodies being positive or negative.160

Probable diagnosis

A negative PCR while IgM against ZIKV is positive which indicates probable ZIKV infection. The IgM result may be false-positive due to cross-reacting IgM antibodies or may be a result of a non-specific reactivity.164 Mother testing results are very important in this regard. Therefore, a positive IgM in the infant makes congenital ZIKV infections very likely if the maternal ZVI is confirmed. While the presence of CSF IgM is very suggestive of congenital ZIKV infections.164Diagnosis unlikely: The congenital infection is unlikely if both PCR and IgM are negative.160 A negative PCR result alone cannot rule out congenital infection transient viremia as it is not known the period of postnatal viral shedding of in utero infected newborns. Some authors suggest the viremic period can reach up to 67 days after birth.165 There is a need for evidence to definitively excluded CZV infection based on negative rRT-PCR and IgM, in infants with known ZV exposure. A negative newborn PCR test may be due to the absence of virus shedding in the urine despite confirmed maternal infection exposure. Moreover, a negative IgM test may be due to delay IgM antibodies release as in congenital rubella and CMV infection.

Differential Diagnosis

Infants suspected to have ZIKV infections should be evaluated for rubella, cytomegalovirus, and toxoplasmosis. Infections other than ZIKV infections frequently show hepatosplenomegaly, thrombocytopenia, and skin lesions.10,81,128 A detailed evaluation of other causes of microcephaly is also required.


The management is supportive as there is no specific antiviral treatment for CZS. The supportive care needs to focus on (a) seizures; (b) feeding difficulties; (c) hypertonia; and (d) hearing loss.

Parents should be provided with key sets of information. Maternal transmission of ZIKV to the fetus may occur during labor and delivery. There are reports of two cases of intrapartum ZIKV transmission from mothers infected within 2–3 days of delivery to the infant. However, these infants were not symptomatic, while the others showed thrombocytopenia and a widespread rash.58,166,167 ZIKV has been detected in breast milk, but there is no documented evidence of transmission in breast milk.154

Testing both the mother and the baby is indicated during the first 14 days after birth if the mother is exposed to ZIKV within 14 days of delivery with ≥2 of the following; (a) rash, (b) conjunctivitis, (c) arthralgia, (d) fever.166 If either or both newborn’s or mother’s symptoms developed within the first week of birth, both newborn serum and urine ZIKV using real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) should be obtained. However, if available, urine from both the mother and newborn should be obtained in the 2nd week and should be evaluated by Zika rRT-PCR. A positive laboratory test confirms the diagnosis.

If the rRT-PCR is negative 3 days after maternal symptoms, test for ZIKV IgM and neutralizing antibody titers. A positive test is suggestive of the diagnosis. Maternal ZIKV IgM and neutralizing antibody titers should be assessed if the newborn is symptomatic, and the mother is asymptomatic. Possible ZIKV exposure is not an indication of lumber puncture, but if the CSF is available for other reasons, a testing for ZIKV RNA using rRT-PCR is appropriate action.166


  • The general pediatrics services should focus on (a) monitoring growth parameters such as weight, length/height, and HC; (b) routine immunizations; (c) anticipatory guidance; (d) psychosocial support; (e) other necessary testing services; and (f) consultations with other specialist services as needed.160

  • Follow-up with experts in (a) hearing and vision; (b) neurology, focusing on seizures, tone abnormalities, and ex vacuo hydrocephalus; (c) developmental services; (d) feeding difficulties, breathing difficulties, choking, or coughing with feeding and assessment for dysphagia; (e) nutrition; and (f) continued supportive services and palliative care.


The prognosis of newborns with CZI is uncertain. The reported mortality rate among live-born infants with confirmed and probable CZI in Brazil is 4–6%.150

The prognosis of severe CZS with microcephaly and severe other cerebral abnormalities is very poor. However, the prognosis of milder forms is not known.112 Nearly 1/3 of the children are either below average developmental scores or have neurosensory abnormalities such as abnormal eye examinations and/or hearing assessments during the second and third years of life.129 Approximately 29% scored below average in a minimum of one developmental assessment, especially language assessments and 2% of children may be in the autism spectrum disorder during the second year of life.

The presence or absence of structural and functional neurologic abnormalities at birth may not predict later neurodevelopmental outcomes.129,133 Approximately ½ of abnormal neurologic examination or abnormal neuroimaging findings at birth may develop normally in the follow-up assessments in their second or third years of life. About 25% of patients who appeared asymptomatic at birth may have delayed neurodevelopmental outcomes with or without abnormal hearing or ophthalmologic outcomes on follow-up.


Protection against Zika virus infections during pregnancy

  • Avoid travel to areas with mosquito transmission of ZV.168176

  • Protection against mosquito bites.177,178

  • Protection against sexual transmission for a partner who traveled to or lives in an area with a risk of ZV.

  • Adherence to standard infection-prevention precautions.

Guidance for couples planning pregnancy

  • Reproductive-age couples in the affected areas should know the risks of transmission of ZV, the consequences of ZVI during pregnancy, and they should consider the possibility of delaying pregnancy.171,174

  • Partners planning to conceive better to avoid or may postpone travel to areas where mosquito transmission of ZVI is likely unless the travel is very essential.179

  • Wait for a minimum of 3 months after a potential exposure prior to a trial of conception with the use of abstinence or condoms during this period.180

  • Those with infertility treatment who require to use of donor sperm or donor egg should only obtain these gametes from laboratories following FDA recommendation for screening guidelines and avoid donors traveling to risky places within 6 months of donation.180 If they are using their own gametes same testing and timing recommendations of the FDA should be followed.113


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