Since its discovery in 19471, Zika virus (ZIKV) transmission has been reported in 76 countries worldwide as of February 2, 20172. In the general population, infection with ZIKV is often either asymptomatic or mildly symptomatic; development of Guillain-Barré syndrome, hospitalization, and death are unusual3. However, infection during pregnancy may lead to adverse fetal and infant outcomes, including congenital Zika syndrome (CZS)4. Characteristics of CZS include anomalies of the brain and cranial morphology, ocular anomalies, congenital contractures, and neurological sequelae4.
Epidemiology and Pathogenesis
ZIKV is a single-stranded RNA flavivirus (genus Flavivirus, family Flaviviridae) that is closely related to dengue as well as other viruses (e.g., West Nile, Japanese encephalitis, yellow fever)5. Analyses of different isolates of ZIKV indicate at least two major lineages (African and Asian), with further differentiation of the former into west and east African strains6,7. ZIKV infection is transmitted by the bite of infected Aedes mosquitoes, including Aedes aegypti and Aedes albopictus8,9. Other modes of transmission include mother-to-child transmission (MTCT), both in utero10,11 and peripartum12, sexual transmission13,14, laboratory exposure15, and transplantation or transfusion of blood or blood products16. ZIKV RNA17 and infective viral particles12,18 have been detected in breast milk, but transmission of ZIKV through breastfeeding has not been reported.
ZIKV was named for the area where it was discovered, the Zika Forest in Uganda1. The first case of natural ZIKV infection in humans was reported in 196415. Prior to 2007, only 16 cases of human infections with ZIKV had been reported15,19,20,21,22,23, at least 3 of which were laboratory-acquired. In 2007, however, an outbreak of ZIKV infection was reported in Yap State, Federated States of Micronesia24. Of 49 confirmed cases of ZIKV infection, symptoms reported by most of the 31 individuals who provided information were macular or papular rash (90%), fever (65%), arthritis or arthralgia (65%), and nonpurulent conjunctivitis (55%)24. In 2013–2014, another ZIKV outbreak occurred in French Polynesia25, where cases of Guillain-Barré syndrome also were observed26. Subsequently, in 2015, an outbreak in Brazil occurred27,28.
In a study in Brazil during the ZIKV epidemic, 119 individuals with laboratory-confirmed ZIKV infection presented with macular or papular rash (97%), pruritus (79%), prostration (73%), headache (66%), arthralgia (63%), myalgia (61%), nonpurulent conjunctivitis (56%), and low back pain (51%)29. Based on various studies of ZIKV outbreaks24,29, clinical illness due to ZIKV infection appears to be generally mild and relatively short-lived. Preliminary data regarding the duration of viremia and of detection of virus in urine and other bodily fluids have been reported30. The median (95th percentile) for the length of time until the end of ZIKV RNA detection was 14 days (54 days) in serum, 8 days (39 days) in urine, and 34 days (81 days) in semen30. Occurrences of Guillain-Barré syndrome31 and other neurologic disorders (e.g., encephalitis and myelitis), hospitalization, and death are unusual3. Although many infections with ZIKV may be asymptomatic, the exact proportion of infected individuals who are symptomatic and asymptomatic is unknown.
After the onset of the ZIKV epidemic in Brazil in 2015, an increased number of infants born with microcephaly were reported there32, and retrospective analyses of data from French Polynesia revealed an increased number of infants with abnormalities, including microcephaly33. An early study of the pathogenicity of ZIKV in animals revealed that the virus was neurotropic in immunodeficient mice34. Since ZIKV RNA and live virus have been found in the brain tissue of microcephalic infants born to women with ZIKV infection during pregnancy10,11,35,36,37, damage to the central nervous system (CNS) observed in infants with in utero exposure to ZIKV has been attributed to direct cellular damage by the virus10,11,35,36,37. Neural progenitor cells appear to be the main target of ZIKV, but other cells, including immature neurons, astrocytes, microglia, and endothelial cells, also may be infected35,38,39,40.
Clinical Manifestations in the Infant
The full spectrum of outcomes of MTCT of ZIKV appears to be broad. Infants with congenital ZIKV infection may be severely abnormal at birth32,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67, or they may appear normal at birth and neurologic abnormalities may be detected later65,68,69.
Severe abnormalities in the fetus and infant, as well as fetal demise, have been described. In a case series of 11 fetuses and infants with congenital ZIKV infection, 27% mortality was observed in the perinatal period, and neurological abnormalities were observed in all 11 cases, including lissencephaly with hydrocephalus, cerebellar hypoplasia, ventriculomegaly, a reduction in cerebral volume, and microcephaly41. A prospective cohort study enrolled 134 symptomatic, ZIKV-infected pregnant women (all exhibited a rash that had developed within the previous 5 days) and reported pregnancy outcomes42. Of the 125 ZIKV-infected women with pregnancy outcome data reported, nine pregnancies (7.2%) ended with fetal demise and 117 live infants were born to 116 women, including one set of twins. Among these infants, 42% had abnormal brain imaging results (e.g., cerebral calcifications, cerebral hypoplasia or atrophy, and ventriculomegaly), other clinical findings (e.g., small for gestational age, microcephaly, hypertonicity, hyperreflexia, clonus, spasticity, contractures, seizures, and abnormal movements), or both. Abnormal findings were reported in all trimesters of pregnancy: 55% reported infection in the first trimester, 52% after second trimester, and 29% after third trimester infection.
Overall, abnormal findings were observed among 46% of children of ZIKV-infected women versus 11.5% of 57 children of ZIKV-uninfected women (P < 0.001)42. In a study of 442 women with completed pregnancies, birth defects were reported among fetuses and infants born to women with possible ZIKV infection during pregnancy43. Birth defects potentially related to ZIKV infection were identified in 26 fetuses or infants (6%). Among 395 live births and 47 pregnancy losses, birth defects were reported for 21 infants and 5 fetuses, respectively. Of the 26 fetuses and infants, 14 had microcephaly and brain abnormalities on neuroimaging, 4 had microcephaly without reported neuroimaging having been performed, 4 had brain abnormalities but no microcephaly, and the remaining ones had the following abnormalities: 2 had encephalocele, 1 had eye abnormalities, and 1 had hearing abnormalities. Brain abnormalities reported included hydrocephaly, ventriculomegaly, cerebral atrophy, abnormal cortical formation, corpus callosum abnormalities, and intracranial calcifications.
Birth defects were reported in 9 of 85 (11%) of completed pregnancies with laboratory evidence of maternal ZIKV infection in the first trimester or the periconceptional period, and in 15 of 211 (7%) of completed pregnancies with laboratory evidence of possible ZIKV spanning multiple trimesters, including the first trimester. No birth defects were reported among pregnancies with ZIKV infection or ZIKV exposure only in the second (76 cases) or third trimester (31 cases)43. The risk of microcephaly with maternal ZIKV infection during the first trimester was previously estimated to be as high as 13.2%44.
In a review of clinical reports of congenital ZIKV infection from French Polynesia, Brazil, the United States, and Spain, characteristics of CZS included certain anomalies of the brain and cranial morphology, ocular anomalies, congenital contractures, and neurological sequelae4. First, severe microcephaly (more than three standard deviations below the mean) among infants with in utero exposure to ZIKV may occur with other abnormalities, constituting the fetal brain disruption sequence45,46. The fetal brain disruption sequence comprises a pattern of defects, including moderate to severe microcephaly, overlapping cranial sutures, prominence of the occipital bone, and scalp rugae45,46. This syndrome is believed to result from partial destruction of the brain during the second or third trimester with subsequent fetal skull collapse, as well as severe neurologic impairment45,46. Although fetal brain disruption syndrome is not unique to CZS, it was reported only rarely before the ZIKV epidemic4.
The neuropathology observed with congenital ZIKV infection is similar to that observed with congenital cytomegalovirus infection47, except for the distribution of intracranial calcifications (subcortical with ZIKV, periventricular with cytomegalovirus)47,48. Other brain anomalies observed with CZS include ventriculomegaly and cerebral hypoplasia or atrophy, as well as manifestations such as seizures, spasticity, hypertonicity, hyperreflexia, clonus, and abnormal movements42.
Several anomalies of the eye have been reported in infants with presumed or confirmed in utero exposure to ZIKV, including microphthalmia, intraocular calcifications, cataracts, chorioretinal atrophy, optic nerve atrophy or other anomalies, and posterior ocular findings32,49,50,51,52,53,54,55,56,57,58,59. Fetal central nervous system abnormalities can lead to decreased fetal movements and contractures60,61, and congenital contractures of one or multiple joints have been reported in fetuses and infants with presumed or confirmed congenital ZIKV infection32,54,55,62,63. Finally, neurological sequelae of congenital ZIKV infection include tremors and posturing (consistent with extrapyramidal dysfunction)32,64,65, hypertonia, spasticity, irritability, hypotonia, and dysphagia32,65. Sensorineural hearing loss also has been reported66,67.
MTCT of ZIKV has been reported among infants, born to mothers with ZIKV infection during pregnancy, who appeared normal at birth but in whom abnormalities were detected later. In various reports65,68,69, children with presumed or confirmed congenital ZIKV infection, but without diagnosed microcephaly at birth and with postnatal development of microcephaly, have been described.
Laboratory confirmation of suspected ZIKV infection involves the detection of viral RNA during acute infection with a nucleic acid amplification test (NAAT) or a serological assay to detect anti-ZIKV immunoglobulin M (IgM) within weeks to months after the acute infection70. Anti-ZIKV IgG assays are in development but are not yet widely available. NAATs such as reverse transcription polymerase chain reaction (RT-PCR) assays can confirm ZIKV infection only transiently after acute infection (e.g., when the patient is viremic)70.
Only preliminary data are available regarding the duration of viremia (the presence of the virus in other bodily fluids), and recommendations as of April 6, 2017, specify NAAT testing within 2 weeks of exposure or symptom onset71,72,73. Serological assays are limited by cross-reactivity; ZIKV antibodies cross-react with other flaviviruses (e.g., dengue, yellow fever, and West Nile viruses), such that current or previous infection with, or vaccination against, another flavivirus often results in false positive or indeterminate ZIKV serology test results70. Although the exact duration of detection of IgM is unknown, ZIKV IgM testing is recommended within 2–12 weeks of exposure or symptom onset71,72,73. (See the “Treatment” section of this chapter for information regarding RT-PCR testing of tissue specimens.)
Diagnostic testing for ZIKV infection in pregnant women with possible ZIKV exposure should be initiated with RT-PCR, IgM assays, or both71. RT-PCR testing of serum or urine should be performed as the first step for two groups of pregnant women: (a) symptomatic women who have had symptoms for less than 2 weeks; and (b) asymptomatic women, not living in an area with active ZIKV transmission, who had possible exposure less than 2 weeks previously71. In these women, a positive RT-PCR assay is interpreted as representing recent ZIKV infection71.
It is recommended that women with a negative ZIKV RT-PCR assay have additional testing (ZIKV, dengue virus IgM assays, or both), and depending upon the results of these assays and whether the individual resides in an area endemic for dengue, neutralizing antibody testing [plaque reduction neutralization test (PRNT)] may be required71. PRNT testing may not discriminate between ZIKV infection and infection with another flavivirus (e.g., in individuals with previous flavivirus exposure, as would be likely in the Commonwealth of Puerto Rico, a U.S. territory, and other dengue-endemic areas)72.
ZIKV and dengue virus IgM assays should be performed as the first step for symptomatic women at 2–12 weeks after symptom onset71. In these women, negative ZIKV and dengue virus IgM assays are interpreted as representing no recent ZIKV infection71. Women with other ZIKV and dengue virus IgM results should undergo further testing (RT-PCR, PRNT, or both)71. Pregnant women are considered to have confirmed recent ZIKV infection based on the following laboratory evidence: (a) ZIKV, ZIKV RNA, or antigens detected in any body fluid or tissue specimen; or (b) ZIKV or dengue virus IgM (positive or equivocal results) in serum or cerebrospinal fluid (CSF) specimens, with a positive PRNT titer against ZIKV and a negative PRNT titer against the dengue virus71.
Laboratory testing to diagnose congenital ZIKV infection is recommended for (a) infants with findings suggestive of congenital ZIKV infection (regardless of maternal ZIKV laboratory testing results); and (b) infants born to ZIKV-positive mothers (i.e., women with ZIKV RNA detected by RT-PCR in any maternal specimen, ZIKV IgM-positive serum results, or both, with PRNT confirmation of neutralizing antibody titers against ZIKV or a flavivirus not otherwise specified)73. ZIKV RT-PCR testing is performed on infant urine and serum specimens, and ZIKV IgM testing is performed on infant serum73. If CSF is obtained for other reasons, it should undergo ZIKV RT-PCR and ZIKV IgM testing73. Ideally, infant testing for congenital ZIKV infection should be performed within the first 2 days of life to help distinguish prenatal from postnatal infection73. The diagnosis of congenital ZIKV infection can be confirmed by detection of viral RNA by RT-PCR assay73. Congenital ZIKV infection is considered probable in infants with positive ZIKV IgM assays (regardless of PRNT results)73.
If the initial infant IgM assay is ZIKV-positive, testing of an infant specimen by PRNT may be necessary (although results will reflect transplacentally transferred maternal antibodies, generally detectable during the first 18 months of life)73. Recent data suggest that PCR and IgM testing may be negative in infants with clinical features consistent with congenital ZIKV infection74. Theoretically, such a situation may result from incomplete testing (e.g., testing performed on suboptimal specimens), late testing (e.g., infection occurred early in gestation, and testing was performed after ZIKV RNA and ZIKV IgM had waned), or failure of the fetus to mount an IgM antibody response. Visit the CDC website for any changes that may have occurred in diagnostic testing recommendations since this book was published: https://www.cdc.gov/zika/index.html.
Currently, there are no antiviral medications to treat ZIKV infection. Symptomatic ZIKV infection can be treated with interventions to ameliorate symptoms (i.e., rest, hydration, and acetaminophen to reduce fever and pain76. (To reduce the risk of bleeding, aspirin and other nonsteroidal anti-inflammatory drugs are not recommended until dengue can be ruled out.)76
The recommended clinical management of pregnant women with confirmed or possible ZIKV infection includes serial fetal ultrasounds every 3–4 weeks during pregnancy to monitor growth and to evaluate fetal neuroanatomy71. Several of the findings associated with congenital ZIKV infection (e.g., intracranial calcifications, ventriculomegaly, microcephaly, abnormalities of the cerebrum cerebellum, corpus callosum, and eyes, and arthrogryposis) may be detected through fetal ultrasound71. (The time period between maternal infection and the development and detection of abnormalities on fetal ultrasound is unknown.)
Amniocentesis could be considered, although only limited information is available regarding the utility of this procedure in terms of diagnosing congenital ZIKV infection; although detection of ZIKV RNA in amniotic fluid can be interpreted as suggestive of fetal infection, its absence does not eliminate the possibly of fetal infection as the sensitivity of this test has not been established71. Finally, persistent detection of ZIKV RNA in maternal serum during pregnancy has been reported75, but the clinical implications of viral RNA persistence are unknown. Following delivery, pathology evaluation of fetal tissue (for fetal loss or stillbirth) and of the placenta and umbilical cord (for live-born infant) may be useful to establish or confirm maternal ZIKV infection in certain situations71. The correlation of placental and umbilical cord findings with infant outcomes is unknown. Pathologic evaluation may include RT-PCR assay, immunohistochemical staining of the placenta or fixed tissue, or both37,71.
The initial evaluation and recommended outpatient management for infants with possible congenital ZIKV infection is based on maternal and infant laboratory testing and clinical findings in the infant73. For infants whose mothers had laboratory evidence of ZIKV infection but whose initial clinical examination did not reveal any abnormalities, the following is recommended prior to the infant’s hospital discharge: physical examination, including weight, length, and head circumference, and neurologic examination; hearing screen; head ultrasound; and infant ZIKV testing73. If the infant ZIKV testing is negative, follow-up throughout infancy comprises routine care, including repeated measurements of head circumference and assessments of neurodevelopment73. If there is laboratory evidence of ZIKV infection, additional recommended evaluations include an ophthalmology examination and auditory brainstem response testing73. Further testing and evaluations during infancy depend upon initial evaluation results73.
For infants whose mothers had laboratory evidence of ZIKV infection and the initial infant clinical examination revealed abnormalities consistent with congenital ZIKV infection, the following are recommended prior to hospital discharge: laboratory testing (complete blood count, metabolic panel, liver function tests); ophthalmology examination; and auditory brainstem response testing73. In addition, advanced neuroimaging should be considered prior to hospital discharge73. If the infant ZIKV testing is negative, evaluation for other causes of birth defects should be considered, with further management as clinically indicated73. If there is laboratory evidence of ZIKV infection, additional recommended evaluations include thyroid screens, neurologic examinations, an ophthalmology examination, and auditory brainstem response testing73. Routine preventive healthcare, including monitoring of feeding and growth, should be provided, along with routine and congenital infection–specific anticipatory guidance, and referral to specialists (including evaluation for other causes of birth defects as needed)73.
For infants whose mothers were not tested, or who were tested outside of the appropriate window (see earlier in this chapter for the durations of the testing windows for ZIKV NAAT and IgM assays), but whose initial clinical examination did not reveal any abnormalities, the following are recommended prior to hospital discharge: maternal ZIKV testing; routine care (physical examination, weight, length, head circumference, and neurological examination); hearing screening; and head ultrasound73. Consideration should be given to testing the placenta for ZIKV73. If there is laboratory evidence of ZIKV infection in the mother, infant ZIKV testing should be performed73. Subsequent infant management should be based upon the infant’s clinical examination and test results73.
For infants whose mothers were not tested, or who were tested outside of the appropriate window, and the initial infant clinical examination revealed abnormalities consistent with congenital ZIKV infection, the following are recommended prior to hospital discharge: maternal ZIKV testing; routine care (physical examination, weight, length, head circumference, and neurological examination); head ultrasound; laboratory testing (complete blood count, metabolic panel, liver function tests); ophthalmology examination; auditory brainstem response testing; and infant ZIKV testing73. In addition, advanced neuroimaging should be considered prior to hospital discharge73. If the infant ZIKV testing is negative, evaluation for other causes of birth defects should be pursued, and further management would be as clinically indicated73.
If laboratory evidence of ZIKV infection of the infant is obtained, additional recommended evaluations include thyroid screens, neurologic examinations, an ophthalmology examination, and additional hearing evaluation73. Routine preventive healthcare, including monitoring of feeding and growth, should be provided, along with routine and congenital infection–specific anticipatory guidance, and referral to specialists (including evaluation for other causes of birth defects as needed)73.
Although efforts to develop ZIKV vaccines are underway, there is not yet a licensed ZIKV vaccine76. Prevention of ZIKV infection relies primarily upon the prevention of vector-borne transmission through mosquito bites and prevention of sexual transmission76. Methods to protect against mosquito bites include wearing long-sleeved shirts and long pants; staying and sleeping in places with air conditioning and window/door screens to keep mosquitoes outside; sleeping under a mosquito bed net if air conditioning and window/door screens are not available or if sleeping outdoors; taking steps to control mosquitoes inside and outside the home (e.g., cleaning, covering, or discarding items that hold water); and using insect repellent77. Use of a U.S. Environmental Protection Agency (EPA)–registered insect repellent with one of the following active ingredients is recommended: DEET, picaridin, IR3535, oil of lemon eucalyptus, or para-menthane-diol77.
To prevent mosquito transmission of ZIKV to other people, it is especially important that individuals who test positive for ZIKV infection should protect themselves from mosquito bites for at least 3 weeks after symptom onset77. Abstinence and the use of barrier methods (e.g., condoms) are recommended for prevention of the sexual transmission of ZIKV78. Pregnant women should not travel to areas with ZIKV transmission risk, but if travel to such areas cannot be avoided, they should discuss such travel with their doctor first79. Methods of preventing mosquito bites while traveling and sexual transmission (both during and after travel) should be implemented79. Aside from primary prevention (i.e., prevention of acquisition of ZIKV infection by a pregnant woman), it is not known how to prevent MTCT of ZIKV infection. To date, there is no evidence that previous infection with ZIKV will affect the outcome of future pregnancies.
Many questions remain regarding the epidemiology, clinical manifestations, diagnosis, treatment, and prevention of ZIKV infection. Only preliminary data are available regarding the duration of viremia (or the presence of ZIKV in other bodily fluids)30. This, in turn, relates to the duration of infectiousness through sexual or vector-borne transmission. Determining the overall rate of and risk factors for MTCT of ZIKV, as well as for severe manifestations of congenital ZIKV infection, are important. For example, one study of microcephalic infants born to ZIKV-infected mothers in Brazil suggested that the earlier maternal symptomatology (specifically, rash) occurred during pregnancy, the smaller the infant’s mean head circumference at birth69.
Additional research to understand the epidemiology of MTCT of ZIKV more completely is urgently needed. An important area for future research is to determine the full range of clinical presentations of ZIKV infection and the proportion of infected individuals who are symptomatic and asymptomatic. Increased availability and specificity of ZIKV IgG assays, especially for screening women of reproductive age for previous exposure to ZIKV (prior to pregnancy) and neonates for in utero exposure to ZIKV, is essential. Development of such IgG assays has been hampered by the problem of cross-reactivity noted for IgM assays: ZIKV antibodies cross-react with other flaviviruses such that infection with, or vaccination against, another flavivirus often results in false positive or indeterminate ZIKV serology test results. Treatment for ZIKV infection, as well as interventions such as vaccines to prevent infection, especially for women of reproductive age and pregnant women, are needed.
Although generally asymptomatic or mildly symptomatic, ZIKV infection during pregnancy may lead to severe adverse fetal and infant outcomes, including the CZS. The full spectrum of outcomes of congenital ZIKV infection seems to be broad, with the clinical manifestations of congenital ZIKV infection appearing to range from asymptomatic infection at birth, with possible later manifestation of significant abnormalities, to severe abnormalities in the fetus and infant.
Although our understanding of pathogenesis, rates, and manifestations of congenital ZIKV infection has improved rapidly and dramatically, much remains unknown or poorly understood regarding this potentially devastating congenital infection. Because of this, a broad research agenda addressing the pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of ZIKV infection is being implemented.
The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
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