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Zika virus infection: Evaluation and management of pregnant women
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Zika virus infection: Evaluation and management of pregnant women
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Aug 03, 2017.

INTRODUCTION — Zika virus is an arthropod-borne flavivirus transmitted predominantly by mosquitoes. This topic will discuss issues related to Zika virus infection in pregnant women. Other issues related to Zika virus infection, including epidemiology, geographic distribution, transmission, clinical findings, differential diagnosis, complications, treatment, and postnatal evaluation of the infant are reviewed separately. (See "Zika virus infection: An overview" and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

DIAGNOSIS OF ZIKA VIRUS INFECTION IN PREGNANT WOMEN

Clinical approach — We diagnose Zika virus infection in pregnant woman based on guidance published by the United States Centers for Disease Control and Prevention (CDC) (described below). Diagnostic approaches may vary depending on available resources.

The diagnostic approach is different in pregnant compared with nonpregnant individuals because Zika virus RNA can persist longer in a pregnant woman's serum (107 days after symptom onset in one case [1]) and because of the offspring’s risk of major CNS anomalies with congenital infection, even if the mother is asymptomatic [2,3]. Persistent maternal viremia has been attributed to viral replication in the placenta or fetus with transmission to maternal blood [1,2].

Screening — At each prenatal visit, health care providers should screen pregnant woman for possible exposure to Zika virus before and during the current pregnancy and possible symptoms of Zika virus infection.

Exposure history — A positive exposure history includes:

Current or recent residence in an area where mosquito-borne transmission of Zika virus infection has been reported

Recent travel to an area where mosquito-borne transmission of Zika virus infection 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 Zika virus infection has been reported. Sexual contact may be vaginal, anal, or oral, and may involve shared sex toys.

Updated information 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.

Sign and symptom history — Women should be asked whether they or their partner have symptoms or signs consistent with Zika virus infection. These include acute onset of:

Rash

Arthralgia

Conjunctivitis

Fever

The true rate of asymptomatic Zika infection is not known, but it is estimated that approximately 20 percent of Zika-infected individuals have these clinical manifestations, which are often mild [4]. They appear 3 to 14 days after exposure to the virus [4]. Signs and symptoms of Zika virus infection are described in detail separately. (See "Zika virus infection: An overview", section on 'Symptoms and signs'.)

Laboratory testing

Symptomatic women — The CDC's diagnostic approach for symptomatic pregnant women is illustrated in the algorithm (algorithm 1) [5]. A Zika virus nucleic acid test (NAT) of serum and urine and IgM testing are performed as soon as possible, through 12 weeks after symptom onset.

Fetal ultrasonography may also be indicated. (See 'Fetal ultrasonography' below.)

Asymptomatic women with limited or ongoing risk of Zika virus exposure — The CDC's diagnostic approach for asymptomatic pregnant women with possible limited or ongoing Zika virus exposure is illustrated in the algorithm (algorithm 2) [5].

Asymptomatic pregnant women with limited possible Zika virus exposure do not warrant routine laboratory testing. As the prevalence of Zika virus 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 similar to that for symptomatic women using the time frame from the last possible exposure [5].

Fetal ultrasonography is indicated in certain situations. (See 'Fetal ultrasonography' below.) If the fetus has ultrasound findings suggesting congenital Zika syndrome, maternal testing with NAT and IgM are indicated [5].

Asymptomatic women with ongoing possible Zika virus exposure (those who reside in or travel at least weekly to an area with mosquito transmission) warrant testing: NAT three times during pregnancy is suggested (at initial prenatal visit and two more times) [5]. The optimal frequency of testing is unclear. Limiting NAT testing to the first and second trimesters improves early identification of infection, but would miss infections acquired in the third trimester, which also can impact offspring. Local levels of Zika virus transmission and laboratory capacity impact this decision. Confirmation of maternal infection can impact the frequency and focus of ultrasound examination as well as decision-making about possible pregnancy termination.

CDC interactive web tool — The CDC has created an interactive web tool (Pregnancy & Zika Testing) to help health care providers in the United States apply recommendations for Zika virus testing, interpret results, and manage pregnant woman with possible exposure to Zika virus. An obstetrical provider toolkit is also available.

The CDC maintains a clinical consultation service (available 24 hours per day, seven days per week) for health care providers evaluating and caring for pregnant women and infants with possible Zika virus infection (telephone 1-800-CDC-INFO or email at zikamch@cdc.gov).

Technical issues

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

Choice of laboratory — Zika virus testing is performed at the CDC Arbovirus Diagnostic Laboratory, most state health departments, and some commercial laboratories. The American College of Obstetricians and Gynecologists (ACOG) recommends that obstetrical providers use laboratories that can perform combined Zika virus real time reverse-transcription polymerase chain reaction (rRT-PCR) and immunoglobulin M (IgM) and plaque reduction neutralization test (PRNT) testing, rather than forwarding negative rRT-PCR specimens for additional testing in another lab [6].

Specimen collection — Serum is required for all diagnostic algorithms. Serum and urine are the primary specimens for diagnosis of Zika virus infection. Plasma, whole blood, cerebrospinal fluid, amniotic fluid, and tissue samples can also be tested.

When drawing blood for Zika virus testing, ACOG recommends that obstetrical providers consider storing additional serum samples in case further testing is needed [6]. The main challenge pertaining to laboratory testing for Zika virus is that the window period for Zika virus identification in blood or urine by polymerase chain reaction is relatively short (within the first two weeks of infection). Some health departments and private laboratories request concurrent testing of urine and serum samples at <2 weeks.

Diagnosis and diagnostic classification — Diagnostic interpretation of laboratory results for suspected Zika virus infection is shown in the table (table 1).

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 and destroys neuronal progenitor cells and, to a lesser extent, neuronal cells at all stages of maturity [7-14]. In the fetal brain, neuronal growth, proliferation, migration, and differentiation are disrupted, thus slowing and impairing normal brain development in utero and in infancy [15].

In the placenta, the virus primarily infects and replicates in placental macrophages (Hofbauer cells), and to a lesser extent cytotrophoblasts [14]. Early gestational age and the Zika virus strain appear to impact the placenta's vulnerability to infection [16]. Viral replication appears to induce type I interferon, pro-inflammatory cytokines, and antiviral gene expression. (See 'Placental histopathology' below.)

Risk of vertical transmission and anomalies — Rates of Zika virus vertical transmission are difficult to determine accurately because virus-specific IgM and PCR are not positive in all congenitally infected newborns. The risk for vertical transmission exists throughout pregnancy and in offspring of both symptomatic and asymptomatic mothers [17-22]. The greatest risk of serious fetal/newborn sequelae appears to be with first- or second-trimester infection, but serious fetal/newborn sequelae also occur with third-trimester infection [18,23-25].

The magnitude of risk of birth defects resulting from in utero exposure to Zika virus is uncertain. Estimates of the overall risk of any birth defect or abnormality among fetuses and infants of women infected with Zika virus during pregnancy vary widely, likely reflecting differences in study design (eg, population studied, thoroughness of ascertainment of infant outcomes, criteria for congenital infection). Two examples are illustrated below:

A prospective study from Rio de Janeiro followed 134 women with confirmed Zika virus infection during pregnancy and 73 women who were not infected (though 42 percent of these women were infected with chikungunya virus [25]. Pregnancy outcomes were available for 125 and 61 women, respectively:

The rate of fetal loss among Zika virus-infected women was 7 percent, similar to the rate in uninfected women.

Among 117 live-born infants of Zika virus-infected women, the overall rate of adverse findings was 42 percent, and included abnormal brain imaging (24 percent), abnormal neurologic examination (21 percent), small for gestational age (9 percent), ocular abnormalities (7 percent), dysphagia (3 percent), microcephaly (3 percent), abnormal hearing assessment (3 percent), abnormal EEG and/or clinical seizures (3 percent), and other dysmorphisms (10 percent).

Adverse outcomes were noted in 55 percent of pregnancies after first trimester maternal infection, 52 percent after second trimester maternal infection, and 29 percent after third trimester maternal infection.

Important strengths of this study are that it was prospective, the infant population was carefully examined (eg, brain imaging studies [CT, MRI] were offered for infants born to mothers who had positive PCR results for ZIKV even in the absence of a structural birth defect), and all other arboviral infections were ruled out at the time the patients presented).  

The CDC identified 2549 pregnant women with Zika virus infection in Puerto Rico and other US territories between January 1, 2016 and April 25, 2017 [26]. Confirmed first trimester Zika virus infection (positive nucleic acid test) was associated with an 8 percent incidence of fetuses/infants with birth defects, compared with 5 percent and 4 percent in the second and third trimesters, respectively. However, not all infants in this cohort had CNS imaging, and several important outcomes have not been reported, such as the number of infants with seizures and/or visual impairment or hearing loss without a structural birth defect. Therefore, these figures likely understate the true risk of any congenital adverse outcome.

An important finding is that structural birth defects were seen with similar frequency in infants born to women with and without clinical symptoms of ZIKV infection during pregnancy. These and other data [27] support the hypothesis that clinical severity during pregnancy is not necessarily associated with a higher frequency of adverse infant outcomes and that maternal virus load, severity of symptoms and signs, presence of pre-existing dengue antibodies do not appear to be predictors of adverse infant.

Clinical manifestations — In utero Zika virus infection can result in serious sequelae related to the central nervous system [2,25,28-35]. In a review of the major findings of 14 studies with adequate radiological assessment of suspected or confirmed Zika virus-infected fetuses, the most common abnormalities among the 66 fetuses were ventriculomegaly (33 percent), microcephaly (24 percent), and intracranial calcifications (27 percent) [10].

Features of congenital Zika virus syndrome described in case reports and small case series are described below. However, the full spectrum of the syndrome is still being investigated [11].

Fetus

Microcephaly — The World Health Organization (WHO), the United States Centers for Disease Control and Prevention, and other scientific groups have concluded that the Zika virus can cause microcephaly [36,37], based on a rapidly increasing body of observational data and identification of Zika virus infection in the cerebrospinal fluid and serum of newborns with microcephaly [28,30,31,38,39].

Microcephaly appears to be a consequence of Zika virus infection early in pregnancy, particularly during the first trimester and early second trimester, but takes weeks to develop [40]. Newborn microcephaly has been reported rarely in the offspring of women infected in the third trimester [25]. In some cases, congenitally infected offspring of women with first or second trimester Zika virus infection have a normal head circumference at birth but subsequently develop microcephaly in the first year of life [15]. 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 [41].

Zika virus has been linked to both disproportionate and proportionate microcephaly [25]. Proportionate microcephaly in Zika virus-affected infants has been identified in those who are small for gestational age, a finding also described in Zika virus congenital syndrome. In proportionate microcephaly, the reduced head circumference is proportionate to the accompanying (and reduced) weight and height parameters. Disproportionate microcephaly, on the other hand, is not accompanied by equally reduced weight or height parameters; the reduction in head circumference is not proportional to the other anthropometric measures [42]. We have observed that if the brain structures are intact, infants with proportionate microcephaly seem to have a better prognosis than infants with disproportionate microcephaly, but further follow-up of large numbers of infants is required to make any firm conclusions.

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 with in utero Zika virus exposure range from 1 to 5 percent [23,25,43]. In one study from Brazil, the risk of microcephaly after maternal Zika virus infection varied according to the region within the country (higher in the northeast) and by epidemic wave (higher in the first wave) [44]. 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 northeastern Brazil could be explained by a higher attack rate in the general population in that region.

Definition of Zika virus-related microcephaly — There is no standard definition for diagnosis of microcephaly. (See "Microcephaly in infants and children: Etiology and evaluation".)

The WHO has defined microcephaly in infants as follows [45-47]: Occipitofrontal circumference (head circumference) greater than two standard deviations below the mean or less than the third percentile based on standard growth charts for sex, age, and gestational age at birth (eg, Intergrowth-21st standards (table 2) [48]).

The United States Centers for Disease Control and Prevention (CDC) also define microcephaly in infants as an occipitofrontal circumference below the 3rd percentile [49]. Although this theoretically identifies 3 percent of 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 cut-off 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 [50].

In utero, 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' occipitofrontal circumference is ≥3rd 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 Zika virus infection may be appropriate. Zika virus-related microcephaly should be suspected if microcephaly is associated with a molecular or epidemiologic link to Zika virus in the absence of other conditions known to cause microcephaly [51]. A molecular or epidemiologic link to Zika virus can be defined as one or more of the following:

Mother had confirmed case of Zika virus infection during pregnancy.

Mother had sexual contact during pregnancy with a person with confirmed Zika virus infection.

Mother had typical clinical manifestations of Zika virus 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 Zika virus infection has been reported).

Zika virus was detected in amniotic fluid via polymerase chain reaction (PCR) or Zika virus RNA was detected in the placenta.

Postmortem detection of Zika virus in fetal brain tissue via PCR.

Central nervous system abnormalities — Other 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 [41]; 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 [33,34,41,52,53]. Redundant scalp skin is a reflection of disruption of fetal brain growth [54].

Positional abnormalities — Positional anomalies, such as club foot and arthrogryposis, have been observed and may be of neurogenic origin [55].

Adverse pregnancy outcomes — Adverse pregnancy outcomes include fetal loss (miscarriage, stillbirth) [25,28,30,56,57], impaired fetal growth [25,57], and hydrops fetalis [33]. Placental insufficiency is the mechanism postulated for fetal loss later in pregnancy.

In one large Brazilian series, the rate of fetal death in Zika-infected pregnancies was 7 percent and overall adverse outcomes were 46 percent versus 11.5 percent among offspring of Zika-negative women [25].

Pregnancies affected by Zika virus do not appear to be at high risk for preterm birth. In one study of 87 mother-infant pairs with confirmed congenital Zika syndrome (71 with microcephaly), the term birth rate was 91 percent [58].

Postnatal findings — Most of the following findings are first identified postnatally, although some may detected prenatally.

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 [29,59-63]. Almost none of these abnormalities are detectable prenatally.

Hearing loss – Hearing loss has been reported in two series [64,65]. In the larger series of 70 children with microcephaly and laboratory evidence of congenital Zika virus infection, five (7.1 percent) had sensorineural hearing loss of varying severity and laterality when tested at 16 to 315 days of age [65]. 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 three standard deviations 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 [64,66]. 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 [55].

Placental histopathology — Although Zika virus 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.

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 [67]. 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; 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 Zika virus, but Zika virus 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 Zika virus, and Zika virus rRT-PCR was positive.

Examination of the placenta from a pregnancy termination at 21 weeks of gestation due to first trimester Zika virus infection revealed prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells [68]. There was no acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhage.

Indications for examination of the placenta are discussed below. (See 'Placenta' below.)

PREGNANCY MANAGEMENT

Nosocomial transmission — Transmission of Zika virus via occupational exposure in a health care setting (eg, clinic, ultrasound suite, antepartum/postpartum/labor unit) has not been described. Standard precautions are appropriate for protection of health care personnel and patients from Zika virus infection in these settings [69]. This is true for the infant being evaluated as well. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Standard precautions'.)

Maternal treatment — There is no specific treatment for Zika virus infection. Management consists of rest and symptomatic treatment including drinking fluids to prevent dehydration and administration of acetaminophen to relieve fever and pain [70].

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 women ≥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 Zika virus infection and associated complications [71].

Fetal ultrasonography — Ultrasound is the major modality used to screen for congenital Zika virus infection. Magnetic resonance imaging (MRI) is more sensitive for diagnosis of fetal brain abnormalities [72], but more costly and less readily available [2]. It is appropriate when clarification of ultrasound findings would impact pregnancy management.

Candidates — Prenatal ultrasonography to evaluate for fetal abnormalities consistent with congenital Zika virus syndrome is recommended for all pregnant women tested for Zika, regardless of laboratory findings [6].

Timing of initial ultrasound examination — The minimum time between occurrence of maternal Zika virus infection and development of sonographic signs suggestive of fetal infection is not known. In women 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 [40,51,73-75].

One group has recommended performing the first ultrasound examination four weeks from the suspected exposure, followed by serial ultrasound examinations every four weeks; at least one ultrasound should be performed between 28 and 33 weeks of gestation [10,76].

Frequency of follow-up ultrasound examinations — The frequency of examination depends on the clinical scenario, and is discussed below and summarized in the table (table 3).

Women with positive laboratory findings — The United States Centers for Disease Control and Prevention (CDC) and ACOG suggest fetal ultrasound examination every three to four weeks to look for signs of congenital Zika virus infection and monitor fetal growth in pregnant women with laboratory evidence of [6,77]:

Recent Zika virus infection

Recent flavivirus infection (specific virus cannot be identified)

Presumptive recent Zika or flavivirus virus infection

Criteria for these diagnostic classifications are described in the table (table 1).

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

Women with negative laboratory findings and no ongoing exposure

Negative results within 12 weeks of symptom onset or possible exposure – If the initial ultrasound examination in these cases is appropriately timed and normal (see 'Timing of initial ultrasound examination' above), follow-up ultrasound examinations are unlikely to reveal signs consistent with congenital Zika virus syndrome and may be omitted [6].

If the initial ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, maternal Zika virus nucleic acid test (NAT) and IgM tests are performed [5]. Clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

Negative results more than 12 weeks from symptom onset or possible exposure – If the initial ultrasound examination in these cases is appropriately timed and normal , one or more follow-up ultrasound examinations is also reasonable given that Zika virus laboratory test results decline over time and may be negative >12 weeks after an acute infection.

If the initial ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, Zika virus nucleic acid test (NAT) and IgM tests are performed [5], and clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

Women with negative laboratory findings and ongoing exposure — If the initial ultrasound examination in these cases is appropriately timed and normal, serial ultrasound examinations every three to four weeks are reasonable, but guidance for monitoring these pregnancies has not been published. The resources and costs involved for frequent testing are a major challenge. In tropical areas where Zika is endemic or may be circulating, frequent ultrasound screening of large numbers of potentially exposed asymptomatic women would not be feasible.

If any ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, Zika virus nucleic acid test (NAT) and IgM tests are performed [5], and clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

Ultrasound procedure — The International Society of Ultrasound in Obstetrics and Gynecology interim guidance on ultrasound for Zika virus infection in pregnancy recommends the following components for ultrasound screening for fetal Zika virus infection [78]:

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 and estimated date of delivery".)

Microcephaly is frequently detected in the mid to late second trimester, and can be an isolated finding. In the United States, the CDC defines microcephaly in infants as head circumference <3rd percentile for gestational age, which can be determined in fetuses using the Intergrowth-21st fetal head circumference reference chart [79]. The Society for Maternal-Fetal Medicine defines isolated fetal microcephaly as head circumference ≥3 standard deviations below the mean for gestational age and considers the diagnosis of pathologic microcephaly certain when the head circumference is >5 standard deviations below the mean for gestational age [80]. 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 (see 'Definition of Zika virus-related microcephaly' above). In addition, at least one study concluded that sonographic estimation of fetal head circumference underestimated the measurement compared with the postnatal measurement [81]. For these reasons, a prenatal diagnosis of microcephaly is presumptive and must be confirmed or excluded during postnatal follow-up.

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 [41].

Assessment for intracranial calcifications. Intracranial calcifications are sometimes evident in the second trimester, but more often in the third trimester. They were most commonly observed at the gray matter-white matter junction in one study [41]. The basal ganglia and/or thalamus were also commonly involved.

Anatomic survey to look for findings that may be associated with Zika virus infection (table 4). Findings may occur with or without microcephaly and intracranial calcifications, and include [36,41,53,66,82]:

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 standard deviations below the mean for gestational age) or not enlarging appropriately, a detailed neurosonographic examination should be performed as fetuses with head circumference in this range due to Zika virus infection will often have additional findings such as periventricular and intraparenchymal echogenic foci, ventriculomegaly, cerebellar hypoplasia, and cortical abnormalities [80]. A sloping forehead when the fetal profile is imaged also suggests developing microcephaly. MRI may detect abnormalities not visible on ultrasound [2,83] and may also be a useful adjunct when intracranial abnormalities are found.

Evaluation for fetal growth restriction, which may be symmetric or asymmetric (see 'Microcephaly' 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 [84] (see "Fetal growth restriction: Diagnosis", section on 'FL/AC ratio'). 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 Zika Virus Syndrome.

Prenatal (fetal) diagnosis — Zika virus rRT-PCR positivity in amniotic fluid is diagnostic of fetal viral exposure but not predictive of outcome. 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 [85].

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

The sensitivity and specificity of Zika virus 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 [21]. The sensitivity of amniocentesis for diagnosis of congenital Zika virus infection 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 Zika virus 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 [10,86-88]. 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). However, amniocentesis this late in gestation may not allow adequate time to arrange termination of pregnancy if desired because of positive results. 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.

A positive rRT-PCR result on amniotic fluid should be considered suggestive of fetal infection [20]. 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.

If the fetus is abnormal and rRT-PCR is negative, evaluation for other causes of the fetal abnormalities should be considered [74]. However, the duration of amniotic fluid PCR positivity is unknown, so a negative rRT-PCR does not definitively exclude fetal Zika virus infection [89].

The potential clinical course of fetal Zika infection was illustrated in a prospective study of eight pregnancies with first-trimester maternal Zika virus infection and subsequent fetal ultrasound findings suggestive of congenital Zika virus syndrome [90]. Abnormalities on ultrasound were first detected at ≥19 weeks of gestation (mean 23 weeks), 9 to 13 weeks after maternal Zika virus symptoms. Amniocentesis was performed after 20 weeks of gestation in all cases and consistently revealed Zika virus RNA in the amniotic fluid at the initial sampling. Repeat amniocentesis was performed in six cases and was negative in two cases, at 344/7 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. If antenatal testing is performed (eg, nonstress test, biophysical profile) and results are abnormal, early delivery may be appropriate depending on the clinical scenario. These tests are described separately. (See "Nonstress test and contraction stress test" and "The fetal biophysical profile".)

The value of umbilical artery Doppler studies for monitoring fetuses with Zika-related growth restriction is unknown. Until more data are available, it is reasonable to monitor growth restricted fetuses with suspected congenital Zika virus infection by umbilical artery Doppler. (See "Fetal growth restriction: Evaluation and management", section on 'Doppler velocimetry'.)

Delivery — Timing and route of delivery are determined according to routine obstetric policies and standards. The appropriate location for delivery should be decided by late third trimester [10].

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

A positive Zika rRT-PCR confirms maternal infection and can be useful when maternal serologic testing is inconclusive (eg, cannot differentiate between Zika virus and other related flaviviruses or has been conducted >12 weeks after possible maternal exposure) and infant Zika virus testing is not definitive, negative, or not performed [91]. A negative placental PCR result does not exclude maternal or fetal Zika virus infection.

The CDC will consider testing for Zika, dengue, 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 5). Testing is not routinely recommended for asymptomatic pregnant women who have recent possible Zika virus exposure but without ongoing possible exposure and who have a live born infant without evidence of possible Zika virus–associated birth defects [5].

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 [92]; detailed instructions are available online.

Neuraxial anesthesia — The anesthesia team should be informed of parturients with Zika virus infection. There is no evidence of maternal risk from placement of neuraxial anesthetics in women 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 [93].

Breastfeeding — Transmission of Zika virus through breast milk has not been reported [54], although the virus has been detected in breast milk [94-96]. ACOG and others have recommended that women continue to breastfeed as the small potential risk of Zika virus transmission through breast milk is outweighed by the known benefits of breastfeeding [6,89,94,97,98]. Thus far, no developmental complications have been observed in otherwise healthy children with postnatal Zika virus infection or exposure [54,99].

Breastfeeding women should take the precautions against acquisition of Zika virus infection, as described below. (See 'Prevention' below.)

Evaluation of fetal loss and stillbirth — Fetal tissue testing is warranted for fetal losses in women with history of Zika exposure, together with either symptoms consistent with Zika virus infection during or within two weeks of exposure or findings of fetal microcephaly. In such cases, Zika virus rRT-PCR and histopathologic examination with immunohistochemical staining should be performed on fetal tissues including the umbilical cord and placenta [20,100]. Instructions for collecting appropriate specimens are available online [101].

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

NEWBORN EVALUATION AND FOLLOW-UP — (See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

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 Zika virus infection, but multiple promising vaccine candidates are under investigation.

A past Zika virus infection is likely to provide protection from future infection. Although there is no evidence that women who have had a past Zika virus infection are at risk of birth defects in future pregnancies, the possibility cannot be definitively excluded [10].

Guidance for pregnant women — To protect against Zika virus infection, pregnant women should:

Avoid travel to areas with mosquito transmission of Zika virus – Given an association between Zika virus exposure during pregnancy and congenital microcephaly, pregnant women should avoid or consider postponing travel to areas where mosquito transmission of Zika virus is ongoing, unless the need for travel is essential [19,102-107].

Updates regarding the geographic distribution of Zika virus, including travel restrictions for pregnant women, 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 Zika virus infection 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".)

Employers should consider reassigning women who indicate they are or may become pregnant, or men who have a sexual partner who is or may become pregnant, to indoor work to reduce the risk of mosquito bites [108,109].

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 Zika virus infection – Most sexual transmissions have been from symptomatic Zika virus infections, although sexual transmission from an asymptomatic man 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 woman 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 women and clinicians should be aware that Zika virus is transmissible via blood products and organ or tissue transplantation [110,111]. 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 Zika virus transmission –Reproductive-age women and men in affected areas should be informed about the risks of transmission of Zika virus, the consequences of Zika virus infection in pregnancy, and consideration of the possibility of delaying pregnancy. Individual decisions to delay pregnancy should consider the local incidence of Zika virus infection, including whether the epidemic has peaked locally [112].

Those who are attempting to conceive should minimize their risk of exposure to Zika virus, similar to pregnant women (see 'Guidance for pregnant women' above).

Women and men who experience symptoms of Zika virus disease should be tested for Zika virus infection: Men with results that indicate recent Zika virus or unspecified flavivirus infection should wait at least six months from symptom onset before attempting conception with their partner and women with these results should wait at least eight weeks from symptom onset before attempting to conceive [113].

Couples not residing in areas with active Zika virus transmission – Couples planning to conceive should avoid or consider postponing travel to areas where mosquito transmission of Zika virus 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 Zika virus transmission has been identified).

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 women. (See 'Guidance for pregnant women' above.)

Couples with potential exposure not residing in areas with active Zika virus transmission – For men who do not live in an area of active Zika virus transmission, the CDC suggests waiting at least six months after a possible exposure via travel to mosquito transmission areas or sexual contact (if asymptomatic) or onset of symptoms of Zika infection (if symptomatic) before attempting conception, and using abstinence or condoms during this period [113]. This recommendation was based on a study that detected Zika virus RNA in semen for as long as 188 days after symptom onset. However, this is a conservative approach since the longest period between symptom onset and sexual contact was shorter (32 to 41 days) among reported cases of sexually transmitted Zika virus infection. (See "Zika virus infection: An overview", section on 'Transmission'.)

For women who do not live in an area of active Zika virus transmission, the CDC suggests waiting at least eight weeks after last possible Zika virus exposure (if asymptomatic) or after symptom onset (if symptomatic) before attempting to conceive. Zika virus persistence in the female genital tract has been reported for up three weeks after symptom onset, but data are limited [114-116].

The CDC does not recommend routine Zika virus testing for asymptomatic nonpregnant women or men with possible Zika virus exposure who are attempting to conceive [4]. Symptomatic women and men 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 FDA recommended screening guidelines and excluding donors that have traveled to at-risk areas within six months of donation [117]. Couples undergoing fertility treatment with their own gametes should follow the same testing and timing recommendations described above for fertile couples planning pregnancy [4].

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 5th to 6th 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 10th to 12th 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

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

Vertical transmission of Zika virus from mother to fetus during pregnancy has been associated with serious sequelae. The greatest risk of serious fetal sequelae is with first-trimester infection, but serious sequelae in offspring can occur after infection in any trimester. In a prospective report of symptomatic women in Brazil, adverse pregnancy outcomes occurred in 55 percent of first-trimester infections, 52 percent in second trimester infections, and 29 percent of third-trimester infections. CNS manifestations in Zika-affected infants appeared to occur in at least one-third to one-half of true (PCR confirmed) cases. (See 'Congenital infection' above.)

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

For evaluation of pregnant women with Zika virus exposure, we use the United States Centers for Disease Control and Prevention's diagnostic approach (table 1 and algorithm 1 and algorithm 2). (See 'Diagnosis of Zika virus infection in pregnant women' above.)

Prenatal ultrasonography to evaluate for fetal abnormalities consistent with congenital Zika virus syndrome is recommended for all pregnant women who have been tested for Zika virus infection, regardless of laboratory findings. (See 'Candidates' above.)

The minimum time between occurrence of maternal Zika virus infection and development of sonographic signs suggestive of fetal infection is not known. In women infected early in pregnancy, ultrasound findings associated with fetal Zika virus 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. At least one ultrasound should be performed between 28 and 33 weeks of gestation. (See 'Timing of initial ultrasound examination' above.)

For pregnant women with laboratory evidence of:

Recent Zika virus infection

Recent flavivirus infection (specific virus cannot be identified)

Presumptive recent Zika or flavivirus infection

Follow-up fetal ultrasound examinations every three to four weeks are recommended to look for signs of congenital Zika virus infection. (See 'Women with positive laboratory findings' above.)

For women with negative laboratory results within 12 weeks of symptom onset and limited possible exposure (see 'Women with negative laboratory findings and no ongoing exposure' above):

If the initial ultrasound examination is appropriately timed and normal, follow-up ultrasound examinations may be omitted.

If the initial ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, maternal Zika virus nucleic acid test (NAT) and IgM tests are performed. Clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

For women with negative laboratory results more than 12 weeks from symptom onset and limited possible exposure (see 'Women with negative laboratory findings and no ongoing exposure' above):

If the initial ultrasound examination is appropriately timed and normal, one or more follow-up ultrasound examinations is reasonable given that Zika virus laboratory test results decline over time and may be negative >12 weeks after an acute infection.

If the initial ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, Zika virus nucleic acid test (NAT) and IgM tests are performed, and clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

For women with negative laboratory results and ongoing risk of acquiring Zika virus infection (see 'Women with negative laboratory findings and ongoing exposure' above):

If the initial ultrasound examination is appropriately timed and normal, serial ultrasound examinations every three to four weeks are reasonable. The resources and costs involved for frequent testing are a major challenge and may not be feasible in all areas.

If any ultrasound examination shows abnormalities consistent with congenital Zika virus syndrome, Zika virus nucleic acid test (NAT) and IgM tests are performed, and clinical management is individualized based on the results of these tests (table 1) and ultrasound findings.

We suggest offering amniocentesis to women who have fetal ultrasound findings suggestive of congenital Zika virus syndrome and/or positive or inconclusive maternal laboratory test results for Zika virus infection, when this information will impact decisions about pregnancy termination or ongoing pregnancy and delivery management. Zika virus rRT-PCR in amniotic fluid is diagnostic of fetal viral exposure, but not predictive of outcome. (See 'Prenatal (fetal) diagnosis' above.)

There is no specific treatment for Zika virus infection, and there is currently no vaccine for prevention. (See 'Prevention' above.)

To protect against Zika virus infection, pregnant women should (see 'Guidance for pregnant women' above):

Avoid travel to areas with known mosquito transmission of Zika virus

Adhere to mosquito protective measures

Adhere to measures to protect against sexual transmission of Zika virus

Adhere to recommendations regarding blood donation

Adhere to recommendations for standard infection precautions

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

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

Use of UpToDate is subject to the  Subscription and License Agreement.

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