Zika virus infection: Evaluation and management of pregnant patients

INTRODUCTION — The Zika virus (ZIKV) is an arthropod-borne flavivirus transmitted predominantly by mosquitoes. Outbreaks of maternal infection in French Polynesia (2013–2014) and Brazil (2015–2016) resulted in reports of congenital infection resulting in serious anomalies and impaired neurodevelopmental outcomes. Whether novel genetic changes in ZIKV at that time increased its teratogenicity or whether its association with congenital anomalies was not previously recognized is unclear [1].

This topic will discuss issues related to Zika virus infection in pregnant individuals, primarily in the United States. Other issues related to ZIKV infection, including epidemiology, geographic distribution, transmission, clinical findings, differential diagnosis, complications, treatment, and postnatal evaluation of the neonate are reviewed separately.

●(See "Zika virus infection: An overview".)

●(See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

DIAGNOSIS OF ZIKA VIRUS INFECTION IN PREGNANT INDIVIDUALS

Overview — We diagnose ZIKV infection in pregnant individuals based on guidance published by the United States Centers for Disease Control and Prevention (CDC), which involves screening followed by laboratory testing in screen-positive individuals, followed by fetal imaging in patients with laboratory-confirmed infection (see 'Approach to maternal laboratory testing and fetal imaging' below). Diagnostic approaches may vary depending on available resources.

The diagnostic approach is different in pregnant compared with nonpregnant individuals for two main reasons:

●ZIKV RNA persists approximately three times longer in a pregnant person's serum [2,3]. Persistent maternal viremia has been attributed to viral replication in the placenta or fetus with transmission to maternal blood [2,4].

●Evaluation for congenital infection (eg, major fetal central nervous system anomalies) need to be considered during pregnancy, even if the mother is asymptomatic [4,5].

Screening — During an epidemic and in endemic areas, screening for exposure and/or signs and symptoms is performed at each prenatal visit.

●Positive history of exposure — At the initial prenatal visit, it is reasonable for health care providers to verbally screen pregnant patients for possible exposure to ZIKV before and during the current pregnancy. A positive exposure history includes:

•Current or recent residence in an area where mosquito-borne transmission of ZIKV has been reported.

•Recent travel to an area where mosquito-borne transmission of ZIKV has been reported.

•Unprotected sexual contact with a person (male or female) who resides in or has traveled to an area where mosquito-borne transmission of ZIKV has been reported. Sexual contact may be vaginal, anal, or oral, and may involve shared sex toys.

Updated information regarding the geographic distribution of ZIKV may be viewed at the United States Centers for Disease Control and Prevention website and the Pan American Health Organization/World Health Organization website.

●Positive history of ZIKV signs and symptoms — If travel-associated exposure occurred or the patient lives in an endemic region, providers should also ask patients whether they or their partner have or have had symptoms or signs consistent with ZIKV infection. These include acute onset of:

•Maculopapular rash (sometimes pruritic)

•Arthralgia

•Conjunctivitis

•Fever (37.8 to 38.5°C)

Other commonly reported clinical manifestations include myalgia and headache [6]. Signs and symptoms appear 3 to 14 days after exposure to the virus and typically last less than a week [7]. Signs and symptoms of ZIKV infection are described in detail separately. (See "Zika virus infection: An overview", section on 'Symptoms and signs'.)

The true rate of asymptomatic ZIKV infection is not known, but it is probably high since it is estimated that only approximately 20 percent of ZIKV-infected individuals have these clinical manifestations and they are often mild [7].

Approach to maternal laboratory testing and fetal imaging

Symptomatic patients — Pregnant patients with symptoms suggestive of ZIKV infection should be tested as soon as possible. The CDC's diagnostic approach for symptomatic pregnant patients is shown in the algorithm (algorithm 1) [8]. Dengue virus and ZIKV are closely related flaviviruses transmitted by mosquitoes. Because they have similar transmission cycles, distribution in the tropics and subtropics, and similar disease manifestations (fever, rash, myalgia, and arthralgia), pregnant patients with a clinically compatible illness should have serum and urine specimens collected for concurrent dengue and ZIKV nucleic acid amplification tests (NAATs) and IgM antibody testing. The specimens should be collected as soon as possible within 12 weeks of symptom onset.

Fetal ultrasonography is indicated in patients with laboratory evidence of ZIKV infection. (See 'Fetal ultrasonography' below.)

Asymptomatic patients with limited or ongoing risk of Zika virus exposure — The CDC's diagnostic approach for asymptomatic pregnant patients with possible limited or ongoing ZIKV (or dengue virus) exposure is shown in the algorithm (algorithm 2) [9].

●Asymptomatic pregnant patients with limited (ie, recent but not ongoing) possible ZIKV exposure do not warrant routine laboratory testing. As the prevalence of ZIKV infection is decreasing, the likelihood of false positive laboratory testing and the subsequent use of unnecessary intervention is increased. However, after discussion of the risks and expected outcomes of testing and local public health recommendations, some patients may choose to be tested based on personal values and preferences. If testing is performed, it should be conducted in a manner similar to that for symptomatic patients using the time frame from the last possible exposure [9].

Fetal ultrasonography is indicated in certain situations (see 'Fetal ultrasonography' below). If the fetus has ultrasound findings suggesting congenital ZIKV syndrome (eg, microcephaly, complex brain malformations), maternal testing with NAAT and IgM are indicated [9].

●Asymptomatic patients with ongoing possible ZIKV exposure (those who reside in or travel at least weekly to an area with mosquito transmission) warrant testing: NAAT three times during pregnancy is suggested (at initial prenatal visit and two more times) [9]. The optimal frequency of testing is unclear. Limiting NAAT testing to the first and second trimesters improves early identification of infection, but would miss infections acquired in the third trimester, which also can affect offspring. Local levels of ZIKV transmission and laboratory capacity impact this decision. Confirmation of maternal infection can inform the frequency and focus of fetal ultrasound examination as well as decision making about possible pregnancy termination.

Asymptomatic patients with incidental suspicious ultrasound findings — If an obstetric ultrasound examination performed for any reason shows fetal abnormalities consistent with congenital ZIKV syndrome, maternal laboratory testing for ZIKV infection should be performed [8,9]. (See "Zika virus infection: An overview", section on 'Diagnosis'.)

CDC resources — The CDC has created a toolkit to help obstetric providers identify, diagnose, and report ZIKV infection in pregnant patients.

The CDC also maintains a clinical consultation service for health care providers evaluating and caring for pregnant individuals and infants with possible ZIKV infection (telephone 1-800-CDC-INFO or email at [email protected]).

Technical issues

Cross-reactivity with other viruses — Serologic interpretation can be difficult in individuals who have resided in dengue endemic areas, because of the significant serologic cross-reactivity between ZIKV and other flaviviruses, especially dengue viruses 1 through 4. Preexisting dengue antibodies due to past symptomatic or asymptomatic infection may yield false-positive ZIKV antibody results. Similarly, ZIKV antibodies also cross-react with dengue antibodies and may yield false-positive dengue antibody results. Diagnostic tests for these infections are discussed in more detail separately. (See "Zika virus infection: An overview", section on 'Diagnosis'.)

Choice of laboratory — In the United States, ZIKV testing is performed at the CDC Arbovirus Diagnostic Laboratory, most state health departments, and some commercial laboratories.

Specimen collection — Serum is required in all diagnostic algorithms, and urine is often tested as well. Some health departments and private laboratories test urine and serum samples concurrently when testing is performed at <2 weeks from exposure. Plasma, whole blood, cerebrospinal fluid, amniotic fluid, and tissue samples can also be tested.

The main challenge pertaining to ZIKV laboratory testing is that the window for virus identification in blood or urine by polymerase chain reaction is relatively short (within the first two weeks of infection).

Maternal diagnosis and diagnostic classification — The diagnosis of ZIKV infection is definitively established by real-time reverse-transcription polymerase chain reaction (rRT-PCR) for ZIKV RNA or by ZIKV serology (ZIKV immunoglobulin M [IgM] and plaque reduction neutralization test [PRNT]). Diagnostic interpretation of laboratory results for suspected ZIKV or dengue virus infection is shown in the table (table 1) [8].

CONGENITAL INFECTION

Pathogenesis — Studies in animals and human placental studies support the hypothesis that maternal infection leads to placental infection and injury, followed by transmission of the virus across the placenta and ultimately to the fetal brain, where it targets neuronal progenitor cells and, to a lesser extent, neuronal cells at other stages of maturity [10-17]. In the fetal brain, neuronal growth, proliferation, migration, and differentiation are disrupted, thus impairing normal brain development in utero and in infancy [18]. The fetal brain may be particularly vulnerable in the first half of pregnancy because this is the period of peak neuronal proliferation and migration. The fetal inflammatory response to ZIKV infection is attenuated or absent, in contrast to the robust response observed with in utero cytomegalovirus, herpes, and rubella infection [19].

In the placenta, the virus primarily infects and replicates in placental macrophages (Hofbauer cells), and to a lesser extent cytotrophoblasts [17]. Early gestational age and the ZIKV strain appear to impact the placenta's vulnerability to infection [20]. Viral replication appears to induce type I interferon, pro-inflammatory cytokines, and antiviral gene expression. (See 'Placental histopathology' below.)

Frequency of vertical transmission — The frequency of maternal-to-fetal transmission of ZIKV is difficult to determine accurately because virus-specific IgM and polymerase chain reaction (PCR) are not positive in all congenitally infected newborns. However, the risk for vertical transmission exists throughout pregnancy and in offspring of both symptomatic and asymptomatic mothers [21-28]. In a cohort study of 130 infants whose mothers had PCR-confirmed symptomatic ZIKV in pregnancy, the vertical transmission rate was 65 percent [27]. These infants were either ZIKV PCR positive in blood and/or urine or had detectable ZIKV IgM. Earlier maternal trimester of infection was associated with positive infant laboratory results but not necessarily clinical disease. Although vertical transmission was frequent, laboratory-confirmed infection in the infants was not necessarily associated with clinical abnormalities. This suggests vertical transmission may occur without causing symptomatic disease in infants. Because not all infants in this series had serial testing performed, vertical transmission rates may be higher than the reported 65 percent.

Others have reported lower rates of vertical transmission. For example, the rate was 26 percent (76/291) in a prospective cohort study from French Guiana [28]. Differences in study design ranging from maternal and infant inclusion and exclusion criteria, type of laboratory testing, and infant follow-up time make it difficult to compare results across different studies.

Potential consequences of vertical transmission — Vertical transmission of ZIKV clearly can result in congenital anomalies (table 2), but the frequency is uncertain. Estimates of the overall risk of any congenital structural anomaly or other abnormality among fetuses and infants of patients with ZIKV infection during pregnancy vary widely (6 to 8 percent in studies in the United States versus over 40 percent in a Brazilian study), likely reflecting differences in study design (eg, population studied, thoroughness of ascertainment of infant outcomes, criteria for congenital infection) [29,30]. Examples of the prevalence of findings from several prospective studies are provided in the table (table 3). In addition to congenital structural anomalies, other potential consequences of vertical transmission include fetal loss (miscarriage, stillbirth), hydrops fetalis, fetal growth restriction, neurologic and positional abnormalities, and impaired neurodevelopment. (See 'Clinical manifestations' below.)

The greatest risk of serious fetal/newborn sequelae appears to be with first- or second-trimester ZIKV infection, but serious fetal/newborn sequelae also occur with third-trimester infection [22,29-34]. Severity of maternal symptoms and signs, maternal virus load, and preexisting dengue antibodies do not appear to be predictors of infant outcome [30,35].

●In a prospective report of symptomatic patients in Brazil, adverse pregnancy outcomes occurred in 55 percent of first-trimester ZIKV infection, 52 percent in second-trimester ZIKV infection, and 29 percent of third-trimester ZIKV infection [29]. Important strengths of this study are that it was prospective, the infant population was carefully examined (eg, brain imaging studies [computed tomography, magnetic resonance imaging] were offered for infants born to mothers who had positive PCR results for ZIKV even in the absence of a structural anomaly), and all other arboviral infections were ruled out at the time the patients presented).

●In a prospective cohort study from the French territories in the Americas that followed 546 pregnancies (555 fetuses) of patients with symptomatic, PCR-confirmed ZIKV infection [34]:

•The diagnosis of neurologic and ocular abnormalities possibly associated with ZIKV was made in 12.7 percent of first-trimester infections, 3.6 percent of second-trimester infections, and 5.3 percent of third-trimester infections.

•Microcephaly (defined as head circumference >2 standard deviations [SD] below mean) was diagnosed most frequently in first-trimester infections. More severe microcephaly (defined as head circumference >3 SD below mean) was observed in nine cases, seven after first-trimester infection, two after second-trimester infection, and zero after third-trimester infection. Both disproportionate and proportionate microcephaly were observed after any trimester of maternal infection, which suggests that ZIKV might affect fetal growth instead of, or in addition to, its destructive effect on the brain.

•The diagnosis of any of the severe neurologic anomalies included in the definition of congenital ZIKV syndrome (head circumference >3 SD below the mean, brain abnormalities with a specific pattern of damage [calcifications, ventriculomegaly, or cortical malformations], damage to the back of the eye, joints with limited range of motion, hypertonia that restricts body movement) was 6.9 percent after first-trimester infection, 1.2 percent after second-trimester infection, and 0.9 percent after third-trimester infection.

Background rates of these anomalies in the population before the ZIKV epidemic were not provided, so it is not possible to determine what percentage of the observed findings can be attributed to ZIKV. Nevertheless, the rate of anomalies appears to be elevated in all trimesters.

Clinical manifestations

Fetus — In utero ZIKV infection can result in serious sequelae related to the central nervous system [4,29,36-43]. In a review of the major findings of 14 studies with adequate radiologic assessment of suspected or confirmed ZIKV-infected fetuses, the most common abnormalities among the 66 fetuses were ventriculomegaly (33 percent), microcephaly (24 percent), and intracranial calcifications (27 percent) [13]. Other abnormalities have been identified postnatally but may be difficult or impossible to diagnose prenatally. One-third of infants with any Zika-associated congenital anomaly have more than one anomaly on postnatal examination [30]. (See 'Postnatal findings' below.)

Features of congenital ZIKV syndrome described in case reports and small case series are described below and summarized in the table (table 2). These likely represent the most severe end of the disease spectrum. The full spectrum of the syndrome is still being investigated [14].

Microcephaly — The World Health Organization (WHO), the CDC, and other scientific groups concluded that the ZIKV infection can cause microcephaly [44,45] based on a large body of observational data and identification of ZIKV in the cerebrospinal fluid and serum of newborns with microcephaly [36,38,39,46-48].

Microcephaly is more frequent when ZIKV infection occurs early in pregnancy, particularly during the first trimester and early second trimester, but takes weeks to develop [49,50]. The earliest ultrasound-diagnosed case of ZIKV-associated microcephaly was at 18 weeks of gestation [51]. Newborn microcephaly has been reported rarely in the offspring of individuals infected in the third trimester [29]. In some cases, congenitally infected offspring of individuals with first or second trimester ZIKV infection have a normal head circumference at birth but subsequently develop microcephaly in the first year of life (termed secondary microcephaly) [18]. The lack of microcephaly in some cases is due to hydrocephalus, which keeps the skull expanded despite the relatively small amount of brain tissue present [52].

ZIKV infection has been linked to both disproportionate and proportionate microcephaly [29]. Proportionate microcephaly in ZIKV-affected infants has been identified in those who are small for gestational age, a finding also described in congenital ZIKV syndrome. In proportionate microcephaly, the reduced head circumference is proportionate to the accompanying (and reduced) weight and height parameters. By comparison, disproportionate microcephaly is not accompanied by equally reduced weight or height parameters; the reduction in head circumference is not proportional to the other anthropometric measures [53]. Both proportional and disproportional microcephaly have similarly high rates of adverse neurologic outcomes [54].

All estimates of microcephaly risk are uncertain because available data are very limited due to poor ascertainment of infection rates (symptomatic and asymptomatic) and rates of microcephaly. As discussed above, estimates of the risk of microcephaly following in utero ZIKV exposure range from 1 to 5 percent [29,31,55]. In Brazil, the risk of microcephaly after maternal ZIKV infection varied according to the region within the country and by epidemic wave (higher in the first wave) [56]. Further study is needed to confirm whether true variations in risk of the congenital syndrome exist, and if so, why. Higher rates of disease in congenitally infected infants in some regions could be explained by a higher attack rate in the general population in that region [57].

Criteria for diagnosis of Zika virus-related microcephaly — ZIKV-related microcephaly should be suspected if microcephaly is associated with a molecular or epidemiologic link to ZIKV in the absence of other conditions known to cause microcephaly [58]. A molecular or epidemiologic link to ZIKV can be defined as one or more of the following:

●Mother had confirmed case of ZIKV infection during pregnancy.

●Mother had sexual contact during pregnancy with a person with confirmed ZIKV infection.

●Mother had typical clinical manifestations of ZIKV infection (one or more of the following: maculopapular pruritic rash, arthralgia, conjunctivitis, or fever) and relevant epidemiologic exposure during pregnancy (residence in or travel to an area where mosquito-borne transmission of ZIKV has been reported).

●ZIKV was detected in amniotic fluid via PCR, or ZIKV RNA was detected in the placenta.

●Postmortem, ZIKV was detected in fetal brain tissue via PCR.

There are no universal standard criteria for defining microcephaly. (See "Microcephaly in infants and children: Etiology and evaluation".)

●The WHO has defined microcephaly in fetuses and infants as follows [59-61]: Occipitofrontal circumference (head circumference) greater than 2 SD below the mean or less than the 3^rd percentile based on standard growth charts for sex, age, and gestational age at birth (eg, Intergrowth-21st standards (table 4) [62]).

●The CDC also define microcephaly in fetuses and infants as an occipitofrontal circumference below the 3^rd percentile or greater than 2 SD below the mean [63].

●By contrast, the Society for Maternal-Fetal Medicine defines isolated fetal microcephaly as head circumference ≥3 SD below the mean for gestational age and considers the diagnosis of pathologic microcephaly certain when the head circumference is >5 SD below the mean for gestational age [64].

Regardless of the criteria used, for in utero diagnosis of ZIKV-induced microcephaly, the occipitofrontal circumference should be disproportionately small in comparison with the abdominal circumference and femur length and not explained by other etiologies or congenital disorders. If the fetus's occipitofrontal circumference is ≥3^rd percentile but is notably disproportionately small compared with the abdominal circumference and fetal length or if central nervous system abnormalities are noted, additional evaluation for ZIKV infection may be appropriate.

Although the CDC and WHO criteria theoretically identify 3 percent of fetuses/infants as possibly abnormal, it is a practical screening tool for microcephaly 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 [65].

Central nervous system abnormalities — Other central nervous system abnormalities can be seen before microcephaly, which is likely the endpoint of central nervous system disease and loss of brain volume [66]. Subtle destructive brain and ocular injuries can also occur in the absence of microcephaly.

Central nervous system abnormalities include ventriculomegaly; intracranial calcifications, especially along the gray matter-white matter junction, which is unusual as calcifications are typically punctate with other congenital infections [52]; extra-axial fluid; abnormal gyral patterns (eg, polymicrogyria); decreased brain parenchymal volume; cortical atrophy and malformation; hypoplasia of the cerebellum, cerebellar vermis, or brainstem; delayed myelination; and thinning or hypoplasia of the corpus callosum [41,42,52,67,68]. Redundant scalp skin may be observed and reflects disruption of fetal brain growth [69]. Infants with severe brain abnormalities may have overlapping sutures.

Neuroimaging abnormalities differ by trimester of maternal ZIKV infection, which is not surprising since first- and second-trimester infections appear to have more serious fetal sequelae than third-trimester infections. In a series of 110 infants with in utero ZIKV exposure, neuroimaging abnormalities occurred in 63 percent of infants born to mothers infected in the first trimester, 13 percent of infants born to mothers infected in the second trimester, and in 1 percent of infants born to individuals infected in the third trimester [50]. The odds of abnormal neuroimaging were 7.9 times greater in children with first-trimester ZIKV exposure as compared with exposures in subsequent trimesters.

In contrast to the central nervous system abnormalities described above, there is only weak evidence of a possible association between ZIKV infection during pregnancy and neural tube defects [34,55,70].

Growth restriction — Infected fetuses may have symmetric or asymmetric growth restriction [29,71]. In contrast to growth restriction related to placental insufficiency, asymmetric growth restriction in congenital ZIKV syndrome may be femur-sparing rather than head-sparing, but head-sparing asymmetric growth restriction can also occur [19].

During the 2015 Brazilian epidemic, 69 of 83 infants (83 percent) with known birth weight were small for gestational age, compared with 8 of the 173 controls (5 percent) [48]. In a United States cohort of individuals with antenatal ZIKV infection, 11.2 percent were small for gestational age, compared with 5.8 percent of controls [72]. (See 'Ultrasound procedure and potential findings' below.)

Positional abnormalities of extremities — Positional anomalies, such as club foot and arthrogryposis, have been observed and are probably neurogenic in origin [73].

Hydrops, fetal loss/death, and preterm birth — Adverse pregnancy outcomes include fetal loss/death (miscarriage, stillbirth) [29,33,36,38,71,74] and hydrops fetalis [41]. Placental insufficiency from injury or infarction is the mechanism postulated for fetal loss later in pregnancy [19]. In one large Brazilian series, the fetal death rate in ZIKV-infected pregnant patients was 7 percent and the overall rates of adverse outcomes in ZIKV-infected and uninfected pregnant patients were 46 and 11.5 percent, respectively [29].

Pregnancies affected by ZIKV infection do not appear to be at high risk for preterm birth (rate <10 percent in two studies [33,74]).

Postnatal findings — Most of the following findings are first identified postnatally, although some may be detected prenatally. A detailed review of these and other postnatal findings in congenital Zika syndrome can be found separately. (See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate", section on 'Clinical features of congenital Zika syndrome'.)

●Ocular abnormalities – Ocular abnormalities are common and may include pigmentary maculopathy, circumscribed chorioretinal atrophy, optic nerve abnormalities, microcornea, microphthalmia, falciform folds, cataracts, retinal dysplasia, persistent fetal vasculature, vascular attenuation, nystagmus, and glaucoma [37,75-79]. Almost none of these abnormalities are detectable prenatally.

●Hearing loss – Hearing loss has been reported in two series [80,81]. In the larger series of 70 children with microcephaly and laboratory evidence of congenital ZIKV syndrome, five (7.1 percent) had sensorineural hearing loss of varying severity and laterality when tested at 16 to 315 days of age [81]. One of the cases may have been related, at least in part, to amikacin therapy. All five children with hearing loss were among the 44 children with severe microcephaly (at least 3 SD below the mean for gestational age and sex). Hearing loss is not detectable prenatally.

●Neurologic and positional abnormalities – Reported neurologic abnormalities include hypertonia, hypotonia, spasticity, hyperreflexia, severe irritability, and seizures [80,82]. These abnormalities are not typically detected prenatally, but some may lead to positional abnormalities, such as club foot and arthrogryposis, which may be detected prenatally, as discussed above [73].

●Cardiac abnormalities – A Brazilian study of infants with in utero exposure to ZIKV reported that 11 percent (13/120) had nonsevere cardiac abnormalities (atrial septal defect, ventricular septal defect, patent ductus arteriosus), and the frequency of these abnormalities was higher in infants whose mothers had a rash in the second trimester of pregnancy, who had abnormal postnatal central nervous system imaging, or were preterm (two infants who were born at 35 and 36 weeks of gestation) [83].

●Later neurodevelopmental outcomes – In a prospective cohort study of 216 Brazilian children monitored since the time of maternal ZIKV infection during pregnancy, 31.5 percent had below-average neurodevelopment and/or abnormal eye or hearing assessments in the second or third year of life [84]. Abnormalities included delays in verbal, cognitive, and/or motor function, and a small number developed features of autism spectrum disorder. An earlier gestational age at the time of ZIKV infection was a significant predictor of these abnormalities: the risk of below average neurodevelopment decreased by 46 percent when infection occurred in the second rather than the first trimester and by another 46 percent when infection occurred in the third rather than the second trimester.

Absence of structural brain abnormalities, microcephaly, or other signs of congenital ZIKV syndrome at birth does not guarantee normal neurodevelopment [85-87]. As an example, in a study of infants exposed to ZIKV in utero, 2 percent of children with severe developmental delay had normal brain imaging at birth, and 16 percent of those with normal development had abnormal brain imaging at birth [87]. These studies underscore the need for long-term follow-up of all children with confirmed or suspected antenatal ZIKV infection.

Placental histopathology — Although ZIKV infects and replicates in the placenta and disrupts the fetoplacental barrier (see 'Pathogenesis' above), case reports suggest that placental inflammation and cell death are not prominent findings, which is in contrast with TORCH infections (Toxoplasmosis or Toxoplasma gondii; Other infections; Rubella; Cytomegalovirus; Herpes simplex virus-2 or neonatal herpes simplex) [88].

●A series from Brazil described histopathological findings in placental tissue from two newborns with microcephaly and severe arthrogryposis who died shortly after birth, tissue from a microcephalic infant who died at age two months, and two placentas from spontaneous abortions [89]. In all cases, the mothers lived in Brazil and had symptoms consistent with ZIKV infection in the first trimester. The infants were born at 36, 38, and 38 weeks of gestation; the miscarriages were at 11 and 13 weeks of gestation. The only placenta available from a live birth was normal. One of the placentas from a miscarriage had no significant findings; immunohistochemical testing of placental tissue was negative for ZIKV, but ZIKV reverse-transcription polymerase chain reaction (rRT-PCR) was positive. The other placenta from a miscarriage showed dense and heterogeneous chorionic villi with calcification, sclerosis, edema, increased perivillous fibrin deposition, and patchy lymphohistiocytic intervillositis. Immunohistochemical testing was positive for ZIKV, and ZIKV rRT-PCR was positive.

●Examination of the placenta from a pregnancy termination at 21 weeks of gestation due to first trimester ZIKV infection revealed prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells [90]. There was no acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhage.

Indications for examination of the placenta and placental studies for diagnosis of ZIKV infection are discussed below. (See 'Disposition of the placenta' below.)

PREGNANCY MANAGEMENT

Nosocomial transmission — Transmission of ZIKV via occupational exposure in a health care setting (eg, clinic, ultrasound suite, antepartum/postpartum/labor unit) has not been described. Standard infection precautions are appropriate for protection of health care personnel and patients from ZIKV infection in these settings [91]. This is true for the infant under evaluation as well. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Standard precautions'.)

Maternal treatment — There is no specific treatment for ZIKV infection. Management consists of rest and symptomatic treatment including drinking fluids to prevent dehydration and administration of acetaminophen to relieve fever and pain [92].

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue infection has been ruled out to reduce the risk of hemorrhage. NSAIDs should also be avoided in pregnant patients ≥32 weeks of gestation to minimize risk for premature closure of the ductus arteriosus. (See "Inhibition of acute preterm labor", section on 'Fetal side effects'.)

The World Health Organization (WHO) has issued initial guidance on psychosocial support for patients and families affected by ZIKV infection and associated complications [93].

Fetal ultrasonography

Test performance — Ultrasound is the major modality used to screen for congenital ZIKV syndrome; however, sensitivity, specificity, and positive and negative predictive values are not well established.

●In a systematic review including 195 fetuses with congenital ZIKV syndrome findings on prenatal ultrasound examination, the abnormalities were confirmed in 78 percent in the newborn period; among the 190 fetuses without congenital ZIKV syndrome findings on prenatal ultrasound examination, 17 percent had congenital ZIKV syndrome abnormalities identified in the newborn period [94].

●In a prospective study of 92 mother-infant pairs in Brazil with polymerase chain reaction (PCR)-confirmed maternal diagnosis of ZIKV infection in pregnancy (97 percent in first or second trimester), abnormal findings on prenatal ultrasonography had 49 percent sensitivity and 68 percent specificity for association with composite adverse neonatal outcomes; when only ZIKV-associated abnormal prenatal ultrasonography results were considered (eg, microcephaly, cerebral calcifications, ventriculomegaly, fetal growth restriction), sensitivity fell to 22 percent, and specificity increased to 98 percent [95]. The composite outcome included perinatal death, abnormal finding on neonatal examination, or abnormal finding on postnatal neuroimaging.

These findings suggest that normal prenatal ultrasonography has limited ability to predict a normal neonatal outcome in the setting of maternal ZIKV infection in the second and third trimesters. However, limitations of available studies need to be considered, such as the short interval between patient-reported symptoms and ultrasound examination in some patients, inclusion bias due to high attrition rates, and ascertainment bias due to the challenges of comprehensive postnatal testing [96].

Magnetic resonance imaging (MRI) appears to be more sensitive for diagnosis of fetal brain abnormalities [97] but is more costly and less readily available [4]. It is appropriate when clarification of ultrasound findings would impact pregnancy management.

Candidates — Prenatal ultrasonography to evaluate for fetal abnormalities consistent with congenital ZIKV syndrome is recommended for all pregnant patients in whom laboratory testing (real-time reverse-transcription polymerase chain reaction [rRT-PCR] for ZIKV RNA and/or ZIKV-specific IgM) is suggestive or diagnostic of possible ZIKV (table 1) [98,99].

In the United States, pregnant patients with possible exposure but without laboratory evidence of ZIKV infection during pregnancy should undergo ultrasound examination as recommended for routine prenatal care [98]. However, if new cases of congenital ZIKV syndrome are reported in the United States through ongoing surveillance, then closer monitoring of patients with possible exposure but negative laboratory findings may be warranted.

Timing — The optimal timing between exposure and initial sonographic screening and follow-up screening are unknown. The minimum time between occurrence of maternal ZIKV infection and development of sonographic signs suggestive of fetal infection may be as short as two weeks in some cases [98]. In patients infected early in pregnancy, ultrasound findings associated with fetal infection may be detected as early as 18 to 20 weeks of gestation, but are usually detected in the late second and early third trimesters of pregnancy [49,58,100-102].

A reasonable recommendation is to perform the first ultrasound examination four weeks from the suspected exposure, followed by serial ultrasound examinations every four weeks, ensuring that at least one ultrasound is performed between 28 and 33 weeks of gestation [13,103]. However, the United States Centers for Disease Control and Prevention (CDC) has stated that clinicians may consider extending the time interval between ultrasound examinations in accordance with patient preferences and clinical judgment, given that this recommendation is not based on data specific to congenital ZIKV [98]. One study of patients with confirmed ZIKV infection in Colombia found the interval between infection and detection of microcephaly ranged between 15 and 24 weeks with a median time of 18 weeks [49].

If the ultrasound examination is abnormal, amniocentesis for diagnosis of fetal infection should be considered. (See 'Prenatal (fetal) diagnosis' below.)

Ultrasound procedure and potential findings — The International Society of Ultrasound in Obstetrics and Gynecology interim guidance on ultrasound for ZIKV in pregnancy recommends the following components for ultrasound screening for fetal ZIKV infection [104]:

●Routine biometry to detect microcephaly. Accurate assessment of gestational age early in pregnancy is important for establishing a diagnosis of microcephaly late in pregnancy. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

Microcephaly is frequently detected in the mid to late second trimester and can be an isolated finding. As discussed above, microcephaly is often defined as a head circumference >2 standard deviations (SD) below the mean or <3^rd percentile for gestational age, although the Society for Maternal-Fetal Medicine defines it as head circumference ≥3 SD below the mean for gestational age and considers the diagnosis of pathologic microcephaly certain when the head circumference is >5 SD below the mean for gestational age [64] (see 'Criteria for diagnosis of Zika virus-related microcephaly' above). In severe cases, the skull can appear collapsed, with overlapping sutures and redundant skin folds, intracranial herniation of orbital fat, and clot in the confluence of sinuses [52].

In situations where there is concurrent fetal growth restriction and fetal biometry is altered, assessment of microcephaly in utero may not accurately predict postnatal microcephaly. Furthermore, at least one study concluded that sonographic estimation of fetal head circumference underestimated the measurement compared with the postnatal measurement [105]. For these reasons, a prenatal diagnosis of microcephaly is presumptive and must be confirmed or excluded during postnatal follow-up.

●Assessment for intracranial calcifications. Intracranial calcifications are sometimes evident in the second trimester, but more often in the third trimester. They are most commonly observed at the gray matter-white matter junction [52,98]. The basal ganglia and/or thalamus are also commonly involved [52].

●Anatomic survey to look for findings that may be associated with ZIKV infection (table 5). Findings may occur with or without microcephaly and intracranial calcifications at the gray-white matter junction, and include [44,52,68,82,106]:

•Irregular head shape including a sloping/slanted forehead

•Ventriculomegaly

•Parenchymal calcifications

•Cystic lesions

•Intraventricular adhesions

•Callosal dysgenesis or agenesis

•Cerebellar hypoplasia or vermian dysgenesis

•Enlarged cisterna magna

•Abnormal cortical development with reduced amount of brain parenchyma and increased amount of cerebrospinal fluid around the brain

•Arthrogryposis, club foot

•Microphthalmia

If the head circumference is small (>2 but not ≥3 SD below the mean for gestational age) or not enlarging appropriately over time, a detailed neurosonographic examination should be performed as fetuses with head circumference in this range due to ZIKV infection will often have additional findings such as periventricular and intraparenchymal echogenic foci, ventriculomegaly, cerebellar hypoplasia, and cortical abnormalities [64]. A sloping forehead when the fetal profile is imaged also suggests developing microcephaly. MRI may detect abnormalities not visible on ultrasound [4,107] and may also be a useful adjunct when intracranial abnormalities are found.

●Evaluation for fetal growth restriction, which may be symmetric or asymmetric (see 'Growth restriction' above). Estimation of fetal weight and diagnosis of growth restriction is challenging in the microcephalic fetus since formulas that calculate fetal weight commonly use the biparietal diameter or head circumference measurement. If the fetal head is abnormal, formulas using only femur length and abdominal circumference should be used to estimate fetal weight and monitor growth. The software in most ultrasound equipment can make this adjustment. Online calculators are also available [108]. (See "Fetal growth restriction: Screening and diagnosis".)

Oligohydramnios may be present.

The International Society of Ultrasound in Obstetrics and Gynecology provides a free online webinar to help sonographers with diagnosis of congenital ZIKV syndrome.

Prenatal (fetal) diagnosis — The indications for diagnostic amniocentesis, the appropriate gestational age for testing, and the interpretation of the test results are uncertain. Decisions regarding amniocentesis should be tailored to individual clinical circumstances [109].

We offer amniocentesis to patients who have fetal ultrasound findings suggestive of congenital ZIKV syndrome and/or positive or inconclusive maternal laboratory test results for ZIKV infection, when this information will impact decisions about pregnancy termination or ongoing pregnancy and delivery management.

●Positive amniotic fluid rRT-PCR – A positive rRT-PCR result on amniotic fluid should be considered diagnostic of fetal infection [24]. If the test was performed because of maternal laboratory findings and the fetus appears normal, it is unknown whether a positive amniotic fluid rRT-PCR result is predictive of a subsequent fetal abnormality and, if so, what proportion of infants will have abnormalities.

●Negative amniotic fluid rRT-PCR – A negative rRT-PCR result does not exclude congenital infection. If the fetus is abnormal and rRT-PCR is negative, evaluation for other causes of the fetal abnormalities should be performed [101]. However, since ZIKV RNA may be detected transiently, a negative amniotic fluid test result does not definitively rule out congenital ZIKV syndrome. In a prospective study that included nine confirmed cases of congenital ZIKV syndrome with prenatal sonography showing abnormal central nervous system findings, ZIKV was not detected in amniotic fluid in two cases. In one case, maternal infection was at 7 weeks, and amniocentesis was at 34^3/7ths weeks; in the other case, maternal infection was at 12 weeks, and amniocentesis was at 30^4/7ths weeks [110]. In a systematic review of maternal ZIKV infection, approximately two-thirds of mother-infant pairs who had positive ZIKV nucleic acid testing results on an amniotic fluid specimen had at least one congenital ZIKV syndrome abnormality identified postnatally; however, two-thirds of those with negative amniotic fluid test results also had at least one congenital ZIKV syndrome abnormality identified postnatally [94].

The sensitivity and specificity of ZIKV rRT-PCR testing of amniotic fluid for diagnosis of congenital infection are not known and likely depend on timing of amniocentesis after onset of maternal infection [25]. The sensitivity of amniocentesis for diagnosis of congenital ZIKV syndrome may be higher at ≥21 weeks than earlier in pregnancy because, by analogy with other causes of congenital infection (such as cytomegalovirus and Toxoplasma), it is likely that ZIKV is not shed into amniotic fluid until sufficient time has elapsed following maternal viremia for the virus to breach the placental barrier; this is likely six to eight weeks after maternal infection [13,111-113]. In addition, fetal kidney development must be sufficiently advanced to excrete the virus into the amniotic fluid (fetal urine production accounts for most of the amniotic fluid volume after 18 to 21 weeks of gestation). Therefore, if amniocentesis is performed six to eight weeks after maternal infection and false-negative results are suspected, a repeat amniocentesis later in gestation may be considered. However, amniocentesis this late in gestation may not allow adequate time to arrange termination of pregnancy if desired because of positive results.

The potential clinical course of fetal ZIKV infection was illustrated in a prospective study of eight pregnancies with first-trimester maternal ZIKV infection and subsequent fetal ultrasound findings suggestive of congenital ZIKV syndrome [114]. Abnormalities on ultrasound were first detected at ≥19 weeks of gestation (mean 23 weeks), 9 to 13 weeks after maternal ZIKV infection symptoms. Amniocentesis was performed after 20 weeks of gestation in all cases and consistently revealed ZIKV RNA in the amniotic fluid at the initial sampling. Repeat amniocentesis was performed in six cases and was negative in two cases, at 34^4/7ths and 38 weeks of gestation, respectively. Fetal blood was also sampled and showed transient viremia in 2/4 cases. All eight fetuses had biochemical signs of liver cholestasis (elevated γ-glutamyl transpeptidase), with associated moderate cytolysis (abnormal aspartate aminotransferase) in seven cases; all fetuses were anemic (hemoglobin range 7.6 to 13 g/100 mL).

Antepartum fetal monitoring (nonstress test, biophysical profile) — Infected fetuses are at risk for stillbirth, which may be related to hydrops fetalis or growth restriction, although the exact mechanism is unknown. No data or guidelines for antenatal testing of infected fetus are available. If antenatal testing is performed because of the increased risk for stillbirth and results are abnormal, management is according to routine obstetric policies and standards. (See "Overview of antepartum fetal assessment".)

The value of umbilical artery Doppler studies for monitoring fetuses with ZIKV-related growth restriction is unknown. Until more data are available, it is reasonable to monitor these fetuses with umbilical artery Doppler, in accordance with guidelines for all growth-restricted fetuses. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Fetal surveillance'.)

Labor and delivery — Labor management and timing and route of delivery are determined according to routine obstetric policies and standards. The appropriate location for delivery based on expected resource needs should be decided by the late third trimester [13].

Neuraxial anesthesia — The anesthesia team should be informed of parturients with ZIKV infection. There is no evidence of maternal risk from placement of neuraxial anesthetics in patients with uncomplicated active infection (no Guillain-Barré syndrome), but at least one anesthesia group has suggested that theoretic risk of iatrogenic viral crossing of the blood-brain barrier during neuraxial blockade merits discussion when obtaining informed consent [115].

Disposition of the placenta — In patients with positive or inconclusive ZIKV testing results, the combination of histopathologic examination of the placenta and umbilical cord, with ZIKV immunohistochemical staining on fixed tissue and ZIKV RNA testing (via rRT-PCR) on fixed and frozen tissue, may document fetal infection.

A positive ZIKV rRT-PCR confirms maternal infection and can be useful when maternal serologic testing is inconclusive (eg, cannot differentiate between ZIKV and other related flaviviruses or has been conducted >12 weeks after possible maternal exposure) and infant ZIKV testing is not definitive, negative, or not performed [116]. A negative placental PCR result does not exclude maternal or fetal ZIKV infection.

In the United States, the CDC will consider testing for ZIKV, dengue virus, and chikungunya virus on fixed (preferable) and frozen fetal and placental tissue on a case-by-case basis where this information could add diagnostic value (table 6). Testing is not routinely recommended for asymptomatic pregnant individuals who have recent possible ZIKV exposure but without ongoing possible exposure and who have a live born infant without evidence of possible ZIKV-associated congenital anomalies [9].

If testing is performed, the CDC suggests obtaining at least three full thickness placental samples from middle third of placental disk and at least one from the placental disk margin, a 5 x 12 cm strip of fetal membranes, and at least four 2.5 cm segments of the umbilical cord [117]; detailed instructions are available online.

Breastfeeding — Transmission of ZIKV through breast milk has not been reported [69], although the virus has been detected in breast milk [118-120]. The World Health Organization, CDC, ACOG, and others have recommended that mothers continue to breastfeed as the small potential risk of ZIKV transmission through breast milk is outweighed by the known benefits of breastfeeding [99,118,121,122]. Thus far, no developmental complications have been observed in otherwise healthy children with postnatal ZIKV infection or exposure [69,123].

Breastfeeding patients should take the precautions against acquisition of ZIKV, as described below. (See 'Prevention' below.)

Newborn evaluation and follow-up — (See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

Evaluation of fetal loss and stillbirth for Zika virus — Fetal tissue testing is warranted for fetal losses in patients with history of ZIKV exposure, together with either symptoms consistent with ZIKV infection during or within two weeks of exposure or findings of fetal microcephaly. In such cases, ZIKV rRT-PCR and histopathologic examination with immunohistochemical staining should be performed on fetal tissues including the umbilical cord and placenta [24,124]. Instructions for collecting appropriate specimens are available online [125].

Diagnosis of the etiology of fetal loss or stillbirth helps to inform counseling regarding future pregnancy as recurrent congenital ZIKV syndrome has not been reported.

PREVENTION — The key to preventing infection is avoiding exposure to the virus. Exposure can occur as a result of a bite from an infected mosquito or sexual transmission from an infected partner (male or female). (See "Zika virus infection: An overview", section on 'Transmission'.)

There is no vaccine for prevention of ZIKV infection, but multiple promising vaccine candidates are under investigation.

A past ZIKV infection is likely to provide protection from future infection. Although there is no evidence that individuals who have had a past ZIKV infection are at risk of ZIKV-related congenital anomalies in future pregnancies, the possibility cannot be definitively excluded [13].

Guidance for pregnant patients — To protect against ZIKV infection, pregnant patients should:

●Avoid travel to areas with mosquito transmission of ZIKV – Given an association between ZIKV exposure during pregnancy and congenital microcephaly, pregnant patients should avoid or consider postponing travel to areas where mosquito transmission of ZIKV is ongoing, unless the need for travel is essential [23,99,126-131].

Updates regarding the geographic distribution of ZIKV, including travel restrictions for pregnant patients, 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 geographic distribution of ZIKV is evolving and discussed further elsewhere. (See "Zika virus infection: An overview", section on 'Geographic distribution'.)

●Adhere to mosquito protective measures – Mosquito protective measures should be used day and night. (See "Zika virus infection: An overview", section on 'Mosquito protection'.)

Use of United States Environmental Protection Agency-approved insect repellants (DEET for skin, permethrin for clothing) in pregnancy has no known harmful effects if used according to directions. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

If an employee works outdoors, employers should consider reassigning female employees who indicate they are or may become pregnant or male employees who have a sexual partner who is or may become pregnant to indoor work to reduce the risk of mosquito bites [132,133].

●Adhere to measures (abstinence or condoms) throughout pregnancy to protect against sexual transmission if a partner (male or female) has traveled to or lives in an area with risk of ZIKV – Most sexual transmissions have been from symptomatic ZIKV infection, although sexual transmission from an asymptomatic male has been reported. Risk of sexual transmission (vaginal, oral, anal), including the duration of risk, is reviewed separately. (See "Zika virus infection: An overview", section on 'Sexual transmission'.)

●Adhere to standard infection precautions, especially if the pregnant individual is a health care worker who has exposure to blood, semen, and other potentially infectious materials, including laboratory specimens/samples. (See 'Nosocomial transmission' above.)

In addition, pregnant individuals and clinicians should be aware that ZIKV is transmissible via blood products and organ or tissue transplantation [134,135]. Issues related to blood component and donor screening are discussed separately. (See "Blood donor screening: Laboratory testing", section on 'Zika virus' and "Blood donor screening: Medical history", section on 'Zika virus'.)

Guidance for couples planning pregnancy

●Couples residing in areas with active ZIKV transmission – Reproductive-age females and males in affected areas should be informed about the risks of transmission of ZIKV, the consequences of ZIKV infection in pregnancy, and consideration of the possibility of delaying pregnancy. Individual decisions to delay pregnancy should consider the local prevalence of ZIKV infection, including whether the epidemic has peaked locally [136].

Those who are attempting to conceive should minimize their risk of exposure to ZIKV, similar to pregnant individuals. (See 'Guidance for pregnant patients' above.)

Females and males who experience symptoms suggestive of ZIKV infection should be tested for ZIKV: Males with results that indicate recent ZIKV or unspecified flavivirus infection should wait at least three months from symptom onset before attempting conception with their partner, and females with positive results should wait at least two months from symptom onset before attempting to conceive [99].

●Couples not residing in or visiting areas with active ZIKV transmission – Couples planning to conceive should avoid or consider postponing travel to areas below 6500 feet (2000 meters) where mosquito transmission of ZIKV is ongoing, unless the need for travel is essential (refer to United States Centers for Disease Control and Prevention website and the Pan American Health Organization/World Health Organization website for areas where ZIKV transmission has been identified). Regions above 6500 feet (2000 meters) are excluded from travel precautions, since the mosquitoes that transmit Zika virus are rare in these locations and the risk for mosquito-borne transmission of Zika virus is minimal [137].

If travel is essential, they should take precautions (protection from mosquito bites, use of abstinence/condoms) to avoid exposure to the virus, as described above for pregnant patients. (See 'Guidance for pregnant patients' above.)

●Couples with potential exposure not residing in areas with active ZIKV transmission – For males who do not live in an area of active ZIKV transmission, ACOG suggests waiting at least three months after a possible exposure before attempting conception and using abstinence or condoms during this period [99]. This approach is based on the observation that the longest period between sexual contact and symptom onset was 32 to 41 days among reported cases of sexually transmitted ZIKV infection. (See "Zika virus infection: An overview", section on 'Transmission'.)

For females who do not live in an area of active ZIKV transmission, the CDC suggests waiting at least two months after last possible ZIKV exposure (if asymptomatic) or after symptom onset (if symptomatic) before attempting to conceive. ZIKV persistence in the female genital tract has been reported for up three weeks after symptom onset, but data are limited [138-140].

The CDC does not recommend routine ZIKV testing for asymptomatic nonpregnant females or males with possible ZIKV exposure who are attempting to conceive [7]. Symptomatic females and males should be tested.

●Couples undergoing infertility treatment – Couples undergoing infertility treatment who require the use of donor sperm or donor egg should only obtain these gametes from laboratories following US Food and Drug Administration recommended screening guidelines and excluding donors that have traveled to at-risk areas within six months of donation [141]. Couples undergoing fertility treatment with their own gametes should follow the same testing and timing recommendations described above for fertile couples planning pregnancy [7].

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".)

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 e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Maternal clinical manifestations – Clinical manifestations of Zika virus infection (ZIKV) in pregnant individuals are the same as those in nonpregnant adults: acute onset of fever, rash, arthralgia, conjunctivitis. (See 'Diagnosis of Zika virus infection in pregnant individuals' above.)

●Maternal evaluation and diagnosis

•Health care providers should ask pregnant patients about relevant past and ongoing epidemiologic exposure resulting from residence, travel, or unprotected sexual contact with a person at risk of infection, and about symptoms of ZIKV infection. (See 'Diagnosis of Zika virus infection in pregnant individuals' above.)

•For evaluation of pregnant patients with ZIKV exposure, we use the United States Centers for Disease Control and Prevention's (CDC) diagnostic approach (algorithm 1 and algorithm 2 and table 1). The CDC recommends laboratory testing for pregnant individuals who are symptomatic or those with ongoing ZIKV or dengue virus exposure throughout pregnancy and suggests using shared decision making in asymptomatic individuals with limited exposure. (See 'Diagnosis of Zika virus infection in pregnant individuals' above.)

•Prenatal ultrasonography to evaluate for fetal abnormalities consistent with congenital ZIKV syndrome is recommended for all pregnant patients with laboratory evidence of ZIKV infection. Pregnant patients with possible exposure but without laboratory evidence of ZIKV infection during pregnancy should undergo ultrasound examination as recommended for routine prenatal care. (See 'Candidates' above.)

●Vertical transmission

•Sequelae – Vertical transmission of ZIKV from mother to fetus during pregnancy has been associated with serious sequelae, termed congenital Zika virus syndrome (table 2). The greatest risk of serious fetal sequelae is with first-trimester infection, but serious sequelae in offspring can occur after infection in any trimester. Examples of the prevalence of findings in several prospective studies are provided in the table (table 3). (See 'Congenital infection' above.)

•Fetal sonographic evaluation – The minimum time between occurrence of maternal ZIKV infection and development of sonographic signs suggestive of fetal infection is not known but may be as short as two weeks in some cases. In patients infected early in pregnancy, ultrasound findings associated with fetal ZIKV infection may be detected as early as 18 to 20 weeks of gestation but are usually detected in the late second and early third trimester of pregnancy.

A reasonable recommendation is to perform the first ultrasound examination four weeks from the suspected exposure, followed by serial ultrasound examinations every four weeks, ensuring that at least one ultrasound examination is performed between 28 and 33 weeks of gestation. The CDC has stated that clinicians may consider extending the time interval between ultrasound examinations in accordance with patient preferences and clinical judgment given that this recommendation is not based on data specific to congenital ZIKV syndrome. (See 'Timing' above.)

Although characteristic abnormal findings on prenatal ultrasonography are associated with adverse neonatal outcomes, normal prenatal ultrasonography does not necessarily predict a normal neonatal outcome. (See 'Fetal ultrasonography' above.)

•Fetal diagnosis – We suggest offering amniocentesis to patients who have fetal ultrasound findings suggestive of congenital ZIKV syndrome and/or positive or inconclusive maternal laboratory test results for ZIKV, when this information will impact decisions about pregnancy termination or ongoing pregnancy and delivery management. ZIKV real-time reverse-transcription polymerase chain reaction (rRT-PCR) in amniotic fluid is diagnostic of fetal viral exposure but not predictive of offspring outcome, and a negative test does not exclude fetal infection. (See 'Prenatal (fetal) diagnosis' above.)

●Prevention of maternal infection

•There is no specific treatment for ZIKV infection, and there is currently no vaccine for prevention. Males with recent ZIKV infection or exposure should wait at least three months from symptom onset/exposure before attempting conception with their partner, and females with recent infection or exposure should wait at least two months from symptom onset/exposure before attempting to conceive. (See 'Prevention' above.)

•To protect against ZIKV infection, pregnant individuals should (see 'Guidance for pregnant patients' above):

-Avoid travel to areas with known mosquito transmission of ZIKV

-Adhere to mosquito protective measures

-Adhere to measures to protect against sexual transmission of ZIKV

-Adhere to recommendations regarding blood donation

-Adhere to recommendations for standard infection precautions

●Breastfeeding – Individuals with ZIKV exposure may breastfeed. Transmission of ZIKV through breastfeeding has not been described, although the virus has been detected in breast milk. (See 'Breastfeeding' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Edward RB McCabe, MD, PhD, who contributed to an earlier version of this topic review.