Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate

INTRODUCTION — Zika virus is an arthropod-borne flavivirus transmitted by mosquitoes. Congenital Zika virus infection is associated with severe congenital anomalies. This topic will discuss issues related to newborns congenitally infected with Zika virus. Zika virus infection in pregnant women and other issues related to Zika virus infection, including epidemiology, travel advisories, and infection in older children and adults, are reviewed separately. (See "Zika virus infection: Evaluation and management of pregnant patients" and "Zika virus infection: An overview".)

PATHOGENESIS — Zika virus is a neurotropic virus that particularly targets neural progenitor cells [1]. Murine and human placental studies support the hypothesis that maternal infection leads to placental infection and injury, followed by transmission of the virus to the fetal brain, where it kills neuronal progenitor cells and disrupts neuronal proliferation, migration, and differentiation, which slows brain growth and reduces viability of neural cells [1-7]. Zika virus is also associated with a higher rate of fetal loss throughout pregnancy, including stillbirths. Placental insufficiency is the mechanism postulated to induce fetal loss later in pregnancy; however, significant placental inflammation has not been described [3,8-10]. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Hydrops, fetal loss/death, and preterm birth'.)

HISTOPATHOLOGY — A series from Brazil described histopathologic findings in tissue from two newborns with microcephaly and severe arthrogryposis who died shortly after birth and tissue from a microcephalic infant who died at age two months [11]. In all cases, the mothers lived in Brazil and had symptoms consistent with Zika virus infection in the first trimester. The infants were born at 36, 38, and 38 weeks of gestation. Multiple congenital malformations were noted, including a wide range of brain abnormalities, craniofacial malformations, craniosynostosis, pulmonary hypoplasia, and multiple congenital contractures, consistent with fetal akinesia deformation sequence or severe arthrogryposis. In these three cases, there was immunohistochemical and molecular evidence of virus persistence in the brain. The range of neuropathology included ventriculomegaly, lissencephaly (which commonly aligns with microcephaly), cerebellar hypoplasia, and ventriculomegaly, all of which have been observed in other cases studied [12].

In the histopathologic reports, brains of infant with congenital Zika infection also showed evidence of tissue destruction, including calcifications, gliosis, and necrosis [11]. The presence of necrosis suggests ongoing cellular injury, consistent with the demonstrated continued viral presence. Thus, the patterns of injury are likely to follow from cellular injury at the time of infection as well as subsequent damage as the brain develops. Evidence from cell culture systems places the neuronal precursor cell as a crucial target for Zika virus infection resulting in cell death [13]. Loss of these cells early in development has been reported to substantially reduce the number of neurons generated and result in small brains without cortical gyration [14].

GEOGRAPHIC DISTRIBUTION — Updates regarding the geographic distribution of Zika virus may be viewed at the United States Centers for Disease Control and Prevention website and the Pan American Health Organization/World Health Organization website.

The epidemiology of Zika virus infection is reviewed in detail separately. (See "Zika virus infection: An overview", section on 'Epidemiology'.)

RISK OF VERTICAL TRANSMISSION — The risk for vertical transmission exists throughout pregnancy in mothers with both symptomatic and asymptomatic Zika virus infection; however, the greatest risk of serious fetal sequelae appears to be with first- and second-trimester infection. The risk of vertical transmission is discussed in greater detail separately. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Frequency of vertical transmission'.)

CLINICAL FEATURES OF CONGENITAL ZIKA SYNDROME

In utero — In utero Zika virus infection can result in fetal growth restriction and serious sequelae related to the central nervous system (CNS) [10,12,15-22]. In a review of the major findings of 14 studies with adequate radiologic assessment of suspected or confirmed Zika virus-infected fetuses, the most common abnormalities among the 66 fetuses included [5]:

●Ventriculomegaly (33 percent)

●Microcephaly (24 percent)

●Intracranial calcifications (27 percent)

Fetal loss occurs in approximately 5 to 10 percent of pregnancies with documented Zika virus infection [10,23]. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Fetal ultrasonography'.)

Findings in the newborn

Frequency of congenital abnormalities — Estimates of the overall rates of any abnormality among fetuses and infants exposed to Zika virus during gestation range from 5 to 40 percent [10,23-29]. The wide range likely reflects differences in study design, populations studied, maternal Zika case definition (possible versus confirmed), and the range of clinical abnormalities included. Estimates of the risk of microcephaly with in utero Zika virus exposure range from 1 to 6 percent [10,23,24,26-30]. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Potential consequences of vertical transmission'.)

In a report of the United States Zika Pregnancy and Infant Registry, among the 6799 live-born infants reported to the registry from late 2015 through early 2018, 4.6 percent had one or more Zika-associated congenital abnormalities [29]. In the subset of infants with confirmed maternal Zika virus infection (ie, positive Zika virus nucleic acid amplification test during pregnancy), 6.1 percent had Zika-associated congenital abnormalities. The most common abnormalities were microcephaly (3 percent); corpus callosum abnormalities (0.9 percent); intracranial calcification (0.9 percent); abnormal cortical gyral patterns (0.8 percent); ventriculomegaly (0.8 percent); cerebral or cortical atrophy (0.6 percent); chorioretinal atrophy, scarring, or pigmentary changes (0.7 percent); and optic nerve abnormalities (0.5 percent). Approximately one-third of affected infants had more than one abnormality.

In a meta-analysis of 13 cohort studies from Brazil that included data on 1341 liveborn infants with in utero Zika virus exposure, 15 percent of newborns were small for gestational age (SGA) and 3.5 percent had microcephaly at birth [28]. Among the 565 infants who underwent neuroimaging, 5 percent had at least one abnormal finding, most commonly calcifications and/or ventriculomegaly. Among a subset of approximately 30 percent of the birth cohort who were evaluated at a median age of 11.7 months, the following findings were noted:

●Seizures (6 percent)

●Abnormal tone (7 percent)

●Abnormal ophthalmologic examination (7 percent)

●Failed audiologic test (3 percent)

Clinical findings — The principal clinical features of congenital Zika syndrome (CZS) include microcephaly, facial disproportion, hypertonia/spasticity, hyperreflexia, seizures, irritability, arthrogryposis, ocular abnormalities, and sensorineural hearing loss (SNHL) (picture 1 and table 1) [1,22,31,32]. In a comprehensive review of published reports (including 11 single case reports, 21 case series, and 1 cohort study), the following were identified as unique features of CZS that are rarely seen with other congenital infections [33]:

●Severe microcephaly with partially collapsed skull

●Thin cerebral cortices with subcortical calcifications

●Macular scarring and focal pigmentary retinal mottling

●Congenital contractures (arthrogryposis)

●Marked early hypertonia

However, the full spectrum of the syndrome is broad; more subtle manifestations of Zika virus infection may become apparent as infants age [1].

●Microcephaly – Microcephaly is an important clinical finding in infants with CZS [16,18,19,34-38]; however, normal head circumference does not exclude CZS [39,40]. (See 'Assessment for microcephaly' below.)

Prospective studies have demonstrated that the overall frequency of microcephaly following in utero Zika virus exposure is approximately 1 to 6 percent [10,23,24,26-28,30,41]. Microcephaly following in utero exposure to Zika virus infection can be primary (noted at birth) or secondary (developing in the first months of life) [41].

Both proportionate and disproportionate microcephaly have been reported in infants with CZS. "Proportionate microcephaly" refers to SGA infants who have a small head circumference that is proportionate to their overall small size; "disproportionate microcephaly" refers to infants who have small head circumference with normal weight and length. Neurologic outcomes do not appear to differ between infants with proportional and disproportional microcephaly [42].

Microcephaly appears to be a consequence of Zika infection early in pregnancy; however, proportionate microcephaly has been observed in the offspring of women infected as late as the third trimester of pregnancy [10].

Although rare, resolution of microcephaly has been reported in two children with antenatal Zika virus infection [41]. One had surgically treated craniosynostosis and the other had proportional microcephaly that improved over time as the child grew.

●Craniofacial disproportion – Craniofacial disproportion is seen in most affected infants and is related to the degree of microcephaly (ie, the face appears large in relation to the small head).

●Cutis gyrata – In infants with severe microcephaly, "cutis gyrata," or redundant scalp (skin folds on the scalp due to continued growth of the skin despite poor brain growth), may be observed [1].

●Craniosynostosis – Craniosynostosis may be seen in severely affected infants with CZS [22,43]. In one case series of 23 severely affected infants, 78 percent had a closed anterior fontanel at birth [22].

●SGA – Among infants with in utero Zika virus exposure, approximately 15 percent are SGA at birth [28]. The prevalence of SGA among infants with other clinical findings of CZS is approximately 30 to 40 percent [22,32].

●Seizures – Seizures may occur due to underlying brain malformations, but may also be present in children without apparent CNS abnormalities [10,44,45]. In a systematic review and meta-analysis of 14 observational studies including a total of 903 infants and children diagnosed with CZS, reported rates of seizure disorders among patients with CZS ranged from 35 to 79 percent [45]. Infantile spasms were the primary seizure type; focal seizures were more prevalent in patients who developed epilepsy after one year of age. Seizures in patients with CZS tend to be refractory. In one study of 65 children with CZS-related epilepsy, only 46 percent responded to antiepileptic treatment [46].

●Abnormal neuromotor tone – Infants with CZS commonly exhibit hypertonia, spasticity, hyperreflexia, dysphagia, and feeding difficulties [10,31,47].

●Contractures and orthopedic abnormalities – Arthrogryposis and club foot have been reported and are likely neurogenic in origin (ie, due to fixed posture in utero) [11,48]. Hip dysplasia is a later manifestation related to severe contractures. In one series of 64 children with severe motor impairment due to CZS, 41 percent were diagnosed with hip dysplasia at a median age of 23 months [49].

●Ocular abnormalities – The overall frequency of ocular abnormalities among Zika virus-exposed infants (symptomatic and asymptomatic) is approximately 6 to 7 percent [41,50,51]. Among infants with CZS, approximately one-quarter have ocular abnormalities [52,53].

The most commonly reported eye findings include macular abnormalities (eg, focal pigmentary retinal mottling and chorioretinal atrophy) and optic nerve abnormalities (eg, optic nerve hypoplasia, increased cup-to-disk ratio, and pallor) [33,52-56]. Other reported findings include pigmentary clumping and chorioretinal atrophy outside of the macula; subretinal hemorrhages; coloboma; vascular tortuosity, straightening, and attenuation; abnormal termination of the retinal vessels; and focal areas of vascular dilation [52,53,57-60]. Structural abnormalities (eg, microcornea, microphthalmia, iris colobomas, intraocular calcification, lens subluxation, cataracts), congenital glaucoma, strabismus, and nystagmus have also been reported [17,52-56,59,61-65].

Ophthalmologic lesions in CZS do not appear to progress over time [53]. Cortical visual impairment may be the main cause of blindness in infants with CZS [59,66,67].

Vision impairment is common in infants and children with CZS. In a study of 173 infants with congenital Zika virus infection who underwent eye examination, 30 percent had impaired visual function (ie, defined as inability to fix and follow) [68]. The risk was highest in infants with associated eye abnormalities (of whom 84 percent were unable to fix and follow) and those with microcephaly or other neurologic abnormality (of whom 60 percent were unable to fix and follow). In light of these findings, simple assessment of visual acuity by testing the infant's ability to fix and follow has been proposed as a screening tool for identification of potential symptomatic cases of congenital Zika virus infection in resource-limited settings where pediatric ophthalmologists are not available [68]. (See 'Additional evaluation' below.)

●Hearing loss – Hearing loss has been reported in approximately 5 to 10 percent of infants with in utero Zika virus exposure [28,41,50,69]. Hearing loss is particularly common among infants with microcephaly [69]. Delayed-onset hearing loss has not yet been reported.

●Cardiac anomalies – In two studies including a total of 223 infants with presumed or confirmed CZS, the reported prevalence of congenital heart disease (CHD) was approximately 10 to 15 percent [70,71]. This rate is considerably higher than the prevalence of CHD in the general population (which is approximately 1 percent). Most of the CHD defects in these studies were nonsevere, including secundum atrial septal defects, patent ductus arteriosus, and small muscular or perimembranous ventricular septal defects (VSDs). Only one of the 223 infants had a hemodynamically significant CHD defect (a large membranous VSD). (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis".)

Neuroimaging findings — Neuroradiologic abnormalities are detected in the majority of infants with CZS who undergo neuroimaging. The risk of having neurologic abnormalities on imaging studies is highest in infants born to mothers infected in the first trimester [43].

Findings may include (image 1A-C) [12,21,43,72-74]:

●Intracranial calcifications

●Ventriculomegaly

●Cortical atrophy

●Reduced brain volume

●Delayed myelination

●Simplified gyral patterns (eg, polymicrogyria, pachygyria, lissencephaly)

●Thinning or hypoplasia of the corpus callosum

●Hypoplasia of the brainstem and cerebellum

●Enlargement of the cisterna magna

●Increased extra-axial fluid spaces

Intracranial calcifications most commonly occur at the junction between the cortical and subcortical white matter and may also occur in other locations such as the basal ganglia, thalamus, periventricular region, brainstem, and cerebellum [12,43,73]. The finding of calcification along the gray matter-white matter junction can help distinguish congenital Zika virus infection from other congenital infections (eg, cytomegalovirus) in which calcifications are typically punctate. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Neuroimaging'.)

In a case series of 37 affected infants who underwent follow-up imaging at approximately one year of age, calcifications had diminished in number, size, or density in most children [75]. However, the reduction in calcifications did not correlate with clinical improvement as most patients in this series had severe neurologic impairment; 40 percent went on to develop hydrocephalus and required ventriculoperitoneal shunt placement.

EVALUATION

Overview — Initial evaluation of infants born to mothers with laboratory evidence of Zika virus infection and/or infants with findings suggestive of congenital Zika infection in the setting of a maternal epidemiologic link should include (algorithm 1) [76]:

●A thorough physical examination (with measurement of head [occipitofrontal] circumference, length, and weight; assessment of gestational age [GA]; and examination for neurologic abnormalities and dysmorphic features).

●Laboratory testing to detect Zika virus. (See 'Laboratory evaluation' below.)

●Head ultrasonography. (See 'Neuroimaging' below.)

●Standard newborn hearing assessment. (See "Screening the newborn for hearing loss".)

●Additional evaluation (including comprehensive eye examination, laboratory tests, and specialist consultation) is performed in neonates with positive maternal Zika virus testing and clinical evidence of congenital Zika syndrome (CZS). (See 'Additional evaluation' below.)

Assessment for microcephaly — There is no standard definition for diagnosis of microcephaly. (See "Microcephaly in infants and children: Etiology and evaluation".)

The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) define microcephaly as occipitofrontal circumference (head circumference) more than two standard deviations below the mean (ie, less than the 3^rd percentile) based on standard growth charts for sex, age, and GA at birth (eg, INTERGROWTH-21st standards (table 2)) [77-79]. Severe microcephaly is defined as head circumference more than three standard deviations below the mean [79].

Although this definition of microcephaly identifies 3 percent of infants as possibly abnormal, it is a practical screening tool since percentile growth charts are typically used for assessing growth in pediatric health care, and this is the lowest cutoff on these charts. Both the CDC and WHO recommend careful clinical evaluation of these infants before making a definitive diagnosis of microcephaly and determining appropriate follow-up [80]. If an infant's occipitofrontal circumference is ≥3^rd percentile but is notably disproportionate to the length of the infant, or if the infant has deficits related to the central nervous system, additional evaluation for Zika virus infection may also be appropriate.

It is important to obtain multiple measurements of the occipitofrontal circumference serially over time since inaccurate measurements are common. This was demonstrated in a report from the United States Zika Pregnancy and Infant Registry of 84 infants who initially were reported to have microcephaly (ie, occipitofrontal circumference <3^rd percentile) at birth and who had subsequent serial measurements reported [81]. Only one-third of the infants continued to have microcephaly on subsequent measurements, whereas 45 percent were felt to have inaccurate initial measurements and 23 percent were assessed as having accurate initial measurements that subsequently improved to ≥3^rd percentile.

Laboratory evaluation

Whom to test — Infants who warrant Zika virus laboratory testing include either of the following (algorithm 1) [76]:

●Newborns of mothers with laboratory evidence for Zika virus infection during pregnancy. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Maternal diagnosis and diagnostic classification'.)

●Newborns who have clinical or neuroimaging findings suggestive of CZS and a maternal epidemiologic link suggesting possible transmission (which includes paternal exposure), regardless of maternal Zika virus test results. A normal head circumference does not exclude the possibility of Zika virus congenital syndrome [47].

Tests to obtain — Laboratory testing for Zika virus infection in the neonate includes the following [76,82]:

●Serum and urine for Zika virus RNA via real-time reverse transcription polymerase chain reaction (rRT-PCR).

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

●If cerebrospinal fluid (CSF) is available, test CSF for Zika virus RNA (via rRT-PCR) as well as Zika virus IgM. CSF specimens need not be collected for the sole purpose of Zika virus testing [76,82].

Instructions for collecting and shipping infant serum are available through the CDC website. The initial samples should be collected from the infant within the first few days after birth if possible to distinguish between congenital, perinatal, and postnatal infection. Testing cord blood is discouraged because it can yield false positive results [76]. Testing should be performed early in the newborn period because the window for viral detection is relatively short [83].

Interpretation — Interpretation of Zika virus testing in the newborn is as follows (table 3) [76]:

●Confirmed infection – Detection of Zika virus RNA by rRT-PCR in infant serum, urine, or CSF collected within the first few days of life confirms the diagnosis of congenital Zika virus infection [76]. IgM antibodies may be positive or negative.

●Probable infection – A negative rRT-PCR with positive Zika virus IgM indicates probable congenital Zika virus infection. However, false-positive results can occur from cross-reacting IgM antibodies or nonspecific reactivity [84]. Results of maternal testing are particularly important in this setting. A positive IgM in the infant in the context of confirmed maternal Zika virus infection during pregnancy is highly suggestive of congenital Zika virus infection. A positive IgM in the CSF is also highly suggestive of congenital Zika virus infection.

If the infant's initial IgM is positive but the mother did not have sufficient testing to definitively confirm or exclude Zika virus infection during pregnancy, then additional testing should be performed to exclude a false positive IgM result. (See 'Excluding false positive IgM results' below.)

●Infection unlikely – If both rRT-PCR and IgM are negative, congenital infection is unlikely [76]. A negative rRT-PCR result alone does not exclude congenital infection because viremia may be transient. The duration of viral shedding in newborns infected in utero is not known. A case report described a newborn who was viremic for at least 67 days after birth [85].

Additional data are needed to determine if Zika infection can be definitively excluded on the basis of negative rRT-PCR and IgM, particularly in infants with a known Zika exposure. Some infants may not shed virus in their urine and therefore PCR testing is negative despite confirmed maternal infection by PCR during pregnancy. It is possible that there may be a delay in forming IgM antibodies (as can be seen in congenital rubella and cytomegalovirus infection). Further data are necessary to clarify this question.

Excluding false positive IgM results — Interpretation of serologic findings, particularly ELISA-based techniques, is complex because serologic tests for Zika virus can cross react with dengue antibodies in endemic areas. For this reason, neutralization assays (eg, plaque reduction neutralization test [PRNT] or virus neutralization test [VNT]) may be required for confirmation.

Neutralization tests are particularly useful if the infant has a negative rRT-PCR with positive IgM and the mother did not have sufficient testing performed during pregnancy to definitively confirm or exclude Zika virus infection. In this setting, a positive IgM in the infant may represent true congenital Zika virus infection (true positive), or it may be a false positive due to cross reactivity with dengue antibodies or nonspecific reactivity. The neutralization test confirms the specificity of the antibodies.

Neutralization tests cannot distinguish between maternally transferred antibody versus infant antibody. Thus, a positive Zika virus PRNT or VNT result in the infant indicates that the infant was exposed to Zika virus antenatally. While this supports the diagnosis of congenital infection (particularly if the infant is symptomatic), it does not definitively confirm that the infant is infected.

Studies conducted in children with confirmed congenital Zika infection have demonstrated that neutralizing antibodies do not persist after maternal antibodies wane [86]. Thus, a negative Zika virus PRNT or VNT in a child >12 months old does not exclude antenatal Zika virus infection.

PRNT assays are not performed in routine clinical laboratory tests but may be available through state and local health departments. They are also available through the CDC. PRNT assays are complex and cumbersome and need to be performed in laboratories familiar with this technique. Additional resources for testing are available through the CDC website.

In addition to testing the neonate, maternal serum should be tested for Zika virus IgM and neutralizing antibodies and dengue virus IgM and neutralizing antibodies if this testing was not already performed during pregnancy. Histopathologic examination of the placenta and umbilical cord can also be helpful. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Approach to maternal laboratory testing and fetal imaging' and "Zika virus infection: Evaluation and management of pregnant patients", section on 'Disposition of the placenta'.)

Neuroimaging — All neonates with suspected or possible congenital Zika infection should have head ultrasonography performed as an initial screening imaging study. If any abnormalities are detected, additional neuroimaging with computed tomography (CT) and/or magnetic resonance imaging (MRI) may be warranted to provide further detail. CT is most sensitive for detection of intracranial calcifications. MRI is more sensitive for characterization of structural brain disease. Consultation with a neurologist is advised to guide appropriate neuroimaging.

If the screening head ultrasound is negative or is not interpretable, yet the clinical findings are suspicious for neurologic involvement (eg, seizures, microcephaly, abnormal or asymmetric tone), a more sensitive imaging study should be performed (ie, CT and/or MRI). Consultation with a neurologist is also advised in these circumstances.

Neuroimaging findings typical of CZS are described above. (See 'Neuroimaging findings' above.)

Additional evaluation — For infants with positive maternal laboratory testing for Zika virus and clinical evidence of congenital Zika infection (ie, microcephaly and/or other congenital anomalies consistent with CZS), a comprehensive evaluation should be performed. The initial clinical evaluation can be completed before hospital discharge or as an outpatient, taking into account hospital capabilities and needs of the family. Transfer to a facility with access to pediatric subspecialty care typically is not necessary unless there is an urgent clinical need (eg, refractory seizures, respiratory failure).

The evaluation includes (algorithm 1) [76]:

●Comprehensive eye examination by an ophthalmologist and evaluation for possible cortical visual impairment prior to discharge from the hospital or within one month of birth

●Testing of auditory brainstem response to assess hearing (see "Screening the newborn for hearing loss", section on 'Automated auditory brainstem response')

●Laboratory tests, including complete blood count and metabolic panel with liver function tests

●Consultation with the following specialists are usually indicated:

•A neurologist for comprehensive neurologic examination and determination of appropriate advanced neuroimaging and electroencephalogram. Evaluation by a neurologist should generally occur within one month after birth.

•An infectious disease specialist to assist in the diagnostic evaluation for Zika virus and other congenital infections (eg, syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, herpes simplex virus infection). (See 'Differential diagnosis' below and "Overview of TORCH infections".)

•A clinical geneticist to evaluate for other causes of microcephaly (table 4) and other anomalies, if present.

•Early intervention and developmental specialists.

•Supportive services for the family/caregivers.

●Additional consultations may be warranted based on clinical findings:

•Orthopedist, physiatrist, physical and/or occupational therapists for the management of hypertonia, club foot, and arthrogrypotic-like conditions (if present).

•Lactation specialist, nutritionist, gastroenterologist, or speech or occupational therapist for management of feeding issues.

•Endocrinologist for evaluation for hypothalamic, pituitary, and/or thyroid dysfunction.

•Pulmonologist or otolaryngologist if there are concerns about aspiration.

•Cardiologist if there are features suggestive of cardiac disease (murmur, poor perfusion, cyanosis). The available data suggest that the prevalence of congenital heart disease is relatively high in infants with CZS (10 to 15 percent); however, hemodynamically significant cardiac defects are rare [70,71]. (See "Approach to the infant or child with a cardiac murmur" and "Identifying newborns with critical congenital heart disease".)

For severely affected infants who are receiving palliative care, providers and families may choose to forego some of these consultations and evaluations.

DIAGNOSIS — A definitive diagnosis of congenital Zika virus infection is confirmed by detection of Zika virus RNA by rRT-PCR in infant serum, urine, or cerebrospinal fluid collected within the first two days after birth [76]. IgM antibodies may be positive or negative.

A negative real-time reverse transcription polymerase chain reaction (rRT-PCR) result does not exclude congenital infection. A negative rRT-PCR result with positive Zika virus IgM test result indicates probable congenital Zika virus infection; however, false-positive results can occur from cross-reacting IgM antibodies or nonspecific reactivity [84]. (See 'Interpretation' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for congenital Zika virus infection includes other congenital infections and other causes of microcephaly.

●Other congenital infections – The findings of congenital Zika infection (microcephaly, intracranial calcifications, ocular abnormalities, hearing loss, small for gestational age) could suggest other congenital infections, particularly rubella, cytomegalovirus, and toxoplasmosis. Other congenital infections may have characteristic clinical findings (table 5). In particular, hepatosplenomegaly, thrombocytopenia, and skin lesions are not typical of congenital Zika syndrome (although thrombocytopenia and rash have been reported with perinatal Zika infection) [31,87]. Appropriate virologic and microbiologic studies generally are necessary to make a specific diagnosis. (See "Overview of TORCH infections".)

●Microcephaly – A variety of genetic abnormalities and environmental insults can affect brain development, resulting in microcephaly (table 6). The etiology and evaluation of microcephaly in infants is discussed in detail separately. (See "Microcephaly in infants and children: Etiology and evaluation".)

MANAGEMENT — There is no specific treatment for Zika virus infection and management is supportive. Management of the complications of congenital Zika syndrome is detailed in separate topic reviews:

●Spasticity (see "Cerebral palsy: Overview of management and prognosis")

●Feeding difficulties (see "Neonatal oral feeding difficulties due to sucking and swallowing disorders", section on 'Management approach')

●Hearing loss (see "Hearing loss in children: Treatment")

●Seizures (see "Treatment of neonatal seizures")

FOLLOW-UP — For infants with confirmed or probable congenital Zika infection, important aspects of follow-up care include (algorithm 1) [76]:

●A medical home should be established and visits with the primary care provider should occur monthly for at least the first six months after birth. Important aspects of follow-up include (see "Children and youth with special health care needs", section on 'Framework of care'):

•Monitoring growth parameters, including head circumference (see "Normal growth patterns in infants and prepubertal children", section on 'Evaluation of growth')

•Monitoring development using a standardized, validated developmental screening tool (see "Developmental-behavioral surveillance and screening in primary care")

•Providing routine immunizations (see "Standard immunizations for children and adolescents: Overview")

•Providing anticipatory guidance, psychosocial support, and ensuring infants receive necessary testing and consultations

●If not performed during the birth hospitalization, auditory brainstem response testing and comprehensive ophthalmologic examination should be performed within one month after birth. The timing of follow-up eye examinations is based on the initial findings. (See "Screening the newborn for hearing loss", section on 'Automated auditory brainstem response' and "Vision screening and assessment in infants and children".)

●If not performed during the birth hospitalization, the patient should be referred to a neurologist within one month after birth for comprehensive neurologic examination and determination of need for additional neuroimaging and/or electroencephalogram. The primary care provider should continue to monitor the neurologic examination closely as neurodevelopmental problems can develop later. (See "Detailed neurologic assessment of infants and children".)

●Referrals to a developmental specialist and for early intervention services should be made.

●Infants should be monitored for other clinical features of congenital Zika syndrome that may develop or worsen over the first year after birth (eg, feeding difficulties, seizures, hydrocephalus):

•Infant feedings should be monitored closely, and if there are signs of swallowing dysfunction (eg, prolonged feeding times, breathing difficulties, choking, or coughing with feeding), an assessment for dysphagia should be performed. (See "Aspiration due to swallowing dysfunction in children", section on 'Evaluation'.)

•Signs of increasing intracranial pressure (eg, increasing head circumference, irritability, or vomiting) should prompt neuroimaging to assess for postnatal hydrocephalus. (See "Hydrocephalus in children: Clinical features and diagnosis", section on 'Evaluation'.)

●Continued supportive services should be provided for the family/caregivers. For severely affected infants who are receiving palliative care, providers and families may choose to forego some of the above consultations and evaluations.

PROGNOSIS

●Challenges in predicting long-term outcome – Outcomes for newborns with congenital Zika infection vary depending on the severity of initial findings. Newborns with severe findings of congenital Zika syndrome (CZS) in the newborn period (eg, severe microcephaly, refractory seizures, severe contractures, arthrogryposis) have the highest risk for mortality and long-term disability.

However, normal findings at birth do not always predict normal outcome later in life. In one study, approximately 25 percent of patients who appeared asymptomatic at birth went on to have neurodevelopmental delays and/or abnormal hearing or ophthalmologic assessments on follow-up [41]. Similarly, mild or subtle findings in the newborn period do not necessarily predict later neurodevelopmental outcomes [41,50]. In the same study, approximately one-half of infants who had abnormal neurologic examination or abnormal neuroimaging findings at birth went on to have normal development on follow-up assessments in their second or third years of life [41]. These findings underscore the need for long-term follow-up of all children with confirmed or suspected in utero Zika virus exposure. (See 'Follow-up' above.)

●Mortality – In a large Brazilian case series, the reported mortality rate among live-born infants with confirmed and probable congenital Zika infection ranged from 4 to 6 percent [47]. In one study of 403 infants and children with confirmed or probable CZS who died in infancy or early childhood, most deaths (82 percent) occurred within the first 12 months after birth [88]. Commonly reported causes of death included neonatal respiratory failure (12 percent), sepsis (11 percent), and multiple congenital malformations (5 percent).

●Neurodevelopmental impairment (NDI) – Long-term NDI is common in children with CZS, and may include cognitive impairment, motor impairment (eg, cerebral palsy [CP]), sensory impairment (blindness, hearing loss), and seizure disorders [41,45,89-94]. Rates of NDI in the available reports vary considerably, likely due to differences in the definitions used for NDI and the population studied (some included all children with in utero Zika virus exposure, while others were limited to children diagnosed with CZS).

In a prospective study that followed children with in utero Zika virus exposure into the second and third years of life, nearly one-third of the children had developmental delay(s) and/or neurosensory abnormalities (abnormal eye examinations and/or hearing assessments) [41]. In this study, 28 percent of children scored <85 in at least one domain of the Bayley-III standardized developmental assessment, and 12 percent of children scored <70. The most commonly affected domain was language function. Autism spectrum disorder was diagnosed in 2 percent of the children in this cohort.

NDI is particularly common in children with Zika virus-associated microcephaly; however, NDI can occur among normocephalic children [92,93,95]. In a study of 112 antenatally Zika virus-exposed children who were normocephalic at birth, 9 percent had severe developmental delay (ie, score <70 on the Bayley-III) on testing performed at a mean age of 18 months [92]. Language development was the most commonly affected domain. Infants who had auditory abnormalities identified in early screening hearing tests had higher rates of developmental delay, underscoring the adverse impact of Zika virus-induced hearing impairment on neurodevelopment. In the same cohort, smaller head circumference at birth, even if still within normal limits, was significantly associated with lower Bayley-III scores, highlighting that subtle clinical manifestations of Zika virus infection can identify infants who are at risk for neurodevelopmental delays [95].

Motor impairment occurs primarily among infants who have manifestations of CZS at birth. The most severely affected infants have hypertonia and arthrogryposis in the newborn period. Motor abnormalities can also evolve during infancy and early childhood. In a study of 74 children with CZS without arthrogryposis or other congenital osteoarticular malformations in the newborn period who underwent follow-up neuromotor assessments at age 24 to 48 months, gross motor function was classified as mildly impaired in 8 percent, moderately impaired in 15 percent, and severely impaired in 77 percent [91]. Although there were small developmental improvements detected in some patients, motor impairment in most children was consistent with severe CP. (See "Cerebral palsy: Classification and clinical features".)

PERINATAL AND POSTNATAL INFECTION

Perinatal exposure — Maternal-fetal transmission of Zika virus can occur during labor and delivery. Two cases of intrapartum Zika virus transmission to infants from mothers infected within two to three days of delivery have been reported; one of these infants had no clinical manifestations, and the other had thrombocytopenia and a diffuse rash [87,96]. There are no reports of Zika virus infection acquired by an infant at the time of delivery leading to microcephaly [97]. Zika virus has been identified in breast milk; however, there are no conclusive data to determine whether transmission can occur via this route [98]. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Breastfeeding'.)

Maternal and newborn laboratory testing is indicated during the first two weeks after birth if the mother had relevant epidemiologic exposure within two weeks of delivery and had ≥2 of the following manifestations of Zika virus infection: rash, conjunctivitis, arthralgia, or fever [96].

●If the mother and newborn present <7 days after onset of maternal signs and symptoms, check serum and urine Zika virus RNA by real-time reverse transcription polymerase chain reaction (rRT-PCR) in both. If mother and newborn present 8 to 14 days after onset of symptoms, check urine Zika rRT-PCR in both. A positive maternal test is diagnostic of infection in the mother and confirms perinatal Zika virus exposure in the infant. A positive rRT-PCR test in the infant confirms infection of the infant.

If maternal rRT-PCR is negative and the mother is ≥4 days after the onset of symptoms, check Zika virus IgM and neutralizing antibody titers. A positive test indicates probable infection during pregnancy.

●If the newborn is symptomatic and the mother is asymptomatic, check maternal Zika virus IgM and neutralizing antibody titers.

If newborn cerebrospinal fluid (CSF) is obtained for other reasons, CSF testing for Zika virus RNA (via rRT-PCR) is appropriate; however, concern for possible Zika exposure alone does not necessitate lumbar puncture [96].

Postnatal infection — Infants and children who acquire Zika virus infection postnatally appear to have a mild course, similar to that in adults [96,99]. Typical symptoms include fever, rash, and conjunctivitis. Zika virus infection in children is discussed in greater detail separately. (See "Zika virus infection: An overview", section on 'Children'.)

PREVENTION — Vaccines against Zika virus are in development but none are available for clinical use [100,101]. Prevention efforts are aimed at reducing Zika infection during pregnancy, which is discussed separately. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Prevention'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Zika virus infection" and "Society guideline links: Microcephaly" and "Society guideline links: TORCH infections".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Zika virus infection (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Transmission – Vertical transmission of Zika virus from mother to fetus during pregnancy can be associated with serious sequelae in the fetus and newborn. The greatest risk appears to be with first- and second-trimester infection. (See "Zika virus infection: Evaluation and management of pregnant patients", section on 'Potential consequences of vertical transmission'.)

●Clinical features – The clinical features of congenital Zika syndrome (CZS) include (table 1 and picture 1) (see 'Clinical findings' above):

•Microcephaly – While microcephaly is a key clinical finding; normal head circumference does not exclude CZS (see 'Assessment for microcephaly' above)

•Craniofacial dysmorphisms (eg, craniofacial disproportion, craniosynostosis)

•Neuromotor abnormalities (eg, hypertonia/spasticity, hyperreflexia, irritability)

•Seizures

•Arthrogryposis

•Ocular abnormalities

•Sensorineural hearing loss

•Neuroimaging abnormalities (eg, intracranial calcifications, ventriculomegaly) – Neuroradiologic abnormalities are detected in the most infants with CZS who undergo neuroimaging (image 1A-C) (see 'Neuroimaging findings' above)

●Evaluation – For all infants with suspected or possible congenital Zika virus infection, the initial evaluation includes all of the following (algorithm 1) (see 'Evaluation' above):

•A thorough physical examination (with measurement of head [occipitofrontal] circumference, length, and weight; assessment of gestational age; and examination for neurologic abnormalities and dysmorphic features) (see 'Assessment for microcephaly' above and 'Findings in the newborn' above)

•Laboratory testing for Zika virus infection, which includes the following (see 'Laboratory evaluation' above):

-Serum and urine for Zika virus RNA via real-time reverse transcription polymerase chain reaction (rRT-PCR).

-Serum Zika virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay. If IgM is positive with negative rRT-PCR, neutralization tests are used to confirm the specificity of the antibodies against Zika virus and to exclude a false-positive IgM result. (See 'Excluding false positive IgM results' above.)

-If cerebrospinal fluid (CSF) is available, test CSF for Zika virus RNA (via rRT-PCR) and Zika virus IgM. CSF specimens need not be collected for the sole purpose of Zika virus testing but may be reasonable for evaluation of infants with microcephaly or intracranial calcifications.

•Head ultrasonography (see 'Neuroimaging' above)

•Standard newborn hearing assessment (see "Screening the newborn for hearing loss")

●Additional evaluation – Infants with positive maternal laboratory testing for Zika virus and clinical evidence of CZS should undergo comprehensive evaluation, including ophthalmologic examination, laboratory tests, and specialist consultation (algorithm 1). (See 'Additional evaluation' above.)

●Diagnosis – A definitive diagnosis of congenital Zika virus infection is confirmed by detection of Zika virus RNA by rRT-PCR in samples of serum, urine, or CSF collected within the first few days of life; IgM antibodies may be positive or negative. A negative rRT-PCR result with positive Zika virus IgM test result indicates probable congenital Zika virus infection (table 3). (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis for congenital Zika virus infection includes other congenital infections (table 5) and other causes of microcephaly (table 6). (See 'Differential diagnosis' above and "Overview of TORCH infections" and "Microcephaly in infants and children: Etiology and evaluation".)

●Management – There is no specific treatment for Zika virus infection and management is supportive. Prevention efforts are aimed at reducing Zika infection during pregnancy. (See 'Management' above and "Zika virus infection: Evaluation and management of pregnant patients", section on 'Prevention'.)

●Follow-up – For infants with confirmed or probable Zika virus infection, close follow-up is necessary. The appropriate follow-up evaluation depends upon the clinical findings. All infants should have close monitoring of growth and development (algorithm 1). (See 'Follow-up' above.)

●Prognosis – Outcomes for newborns with congenital Zika infection vary depending on the severity of initial findings. Reported mortality rates among live-born infants range from 4 to 6 percent. Long-term neurodevelopmental impairments are common in children with CZS, and may include cognitive impairment, motor impairment (eg, cerebral palsy [CP]), sensory impairment (blindness, hearing loss), and seizure disorders. (See 'Prognosis' above.)

●Perinatal and postnatal infection – Maternal-fetal transmission of Zika virus can occur during labor and delivery. There are no reports of Zika virus infection acquired by an infant at the time of delivery leading to microcephaly. There are no data to contraindicate breastfeeding, although the virus has been identified in breast milk. Maternal and newborn laboratory testing is indicated during the first two weeks of life if the mother had relevant epidemiologic exposure within two weeks of delivery and had clinical manifestations of Zika virus infection (eg, rash, conjunctivitis, arthralgia, or fever). Infants and children who acquire Zika virus infection postnatally appear to have a mild course, similar to that seen in adults. (See 'Perinatal and postnatal infection' above.)