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Questions and Answers for Healthcare Providers Caring for Infants and Children with Possible Zika Virus Infection

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Summary

CDC updated its interim guidelines for healthcare providers in the United States caring for infants and children with possible congenital or perinatal Zika virus infection in February 2016. These guidelines include recommendations for the evaluation, testing, and management of infants and children with possible Zika virus infection. These interim guidelines will be updated as more information becomes available.
Update: Interim Guidelines for Healthcare Providers Caring for Infants and Children with Possible Zika Virus Infection – United States, February 2016

What is different in these updated guidelines?

Updated guidelines contain a new recommendation to provide routine care to infants with no abnormal findings on prenatal or postnatal ultrasound, normal physical examination and whose mothers were not previously tested for Zika virus infection. Updated guidelines also contain new recommendations for the care of infants and children with possible acute Zika virus disease.

Why is CDC updating clinical guidelines?

CDC continues to evaluate all available evidence and to update recommendations as new information becomes available. CDC’s updated guidelines have been informed by our close collaboration with clinicians, professional organizations, state and local health departments, and many other stakeholders.

When is an infant or child at risk for Zika virus infection?

An infant or child aged <18 years who has traveled to or resided in an area with ongoing transmission is at risk for Zika virus infection. Adolescents might also be exposed to Zika virus through sexual contact with a male partner who traveled to or resided in an affected area. Additionally, an infant whose mother was infected with Zika virus during pregnancy is at risk for Zika virus infection in utero. Infants can also be infected perinatally if the mother has Zika virus infection within approximately 2 weeks prior to delivery.

Zika Virus Transmission in Infants and Children

How is Zika virus transmitted?

Zika virus is transmitted to humans primarily through the bite of an infected Aedes species mosquito. Aedes mosquitoes are aggressive daytime biters and feed both indoors and outdoors. They can also bite at night. Zika virus can be transmitted from a pregnant mother to her fetus during pregnancy (congenital  transmission) or around the time of birth (perinatal transmission). We do not know how often perinatal Zika transmission occurs. Additionally, spread of the virus through sexual contact and blood transfusion has been reported. Organ or tissue transplantation, and certain fertility treatments pose theoretical risks for Zika virus transmission.

What is the difference between congenital and perinatal transmission of Zika virus?

Congenital or intrauterine transmission of Zika virus occurs when a woman is infected with Zika virus during her pregnancy, but before delivery, and the virus passes to the fetus. Perinatal transmission of Zika virus occurs when a woman is infected with the Zika virus within approximately 2 weeks of delivery, and the virus passes to the infant at or around the time of delivery. When an infant acquires Zika virus infection perinatally, the infant may develop symptoms such as maculopapular rash, conjunctivitis, arthralgia, and fever.

If a mother had Zika virus infection during pregnancy or currently has Zika virus infection, should she breastfeed her infant?

Zika virus has been identified in breast milk, but infant Zika virus infection associated with breastfeeding has not been reported. Current evidence suggests that the benefits of breastfeeding outweigh the theoretical risk of Zika virus infection transmission through breast milk. CDC encourages mothers with Zika virus infection and mothers living in areas with ongoing Zika virus transmission to breastfeed their infants.

Zika Virus Testing for Infants and Children

When should an infant with possible congenital infection be tested for Zika virus?

For infants with possible congenital Zika virus infection who were born to mothers who were potentially exposed to Zika virus (i.e., through travel to or residence in an area of active Zika virus transmission or through sexual contact with a male partner who traveled to or resided in an area of active Zika virus transmission), testing should be guided by (1) whether the infant has microcephaly, intracranial calcifications, or other brain or eye abnormalities consistent with Zika virus disease detected prenatally or postnatally and (2) the mother’s Zika virus testing results.

For infants with findings consistent with congenital Zika virus infection (microcephaly, intracranial calcifications, brain and eye abnormalities detected at birth), Zika virus testing is recommended within 48 hours of birth, if possible.

For infants without evidence of microcephaly, intracranial calcifications, brain and eye abnormalities detected at birth, Zika virus testing is generally recommended under the following circumstances: (1) if the mother tested positive for Zika virus infection, or (2) if the mother had inconclusive Zika virus test results. The results of previous prenatal ultrasounds and maternal Zika virus testing should be reviewed and a thorough newborn physical examination, including careful measurement of head (occipitofrontal) circumference, length, and weight, should be performed. For infants without findings consistent with congenital Zika virus infection and whose mothers either tested negative for Zika virus infection or were not tested for Zika virus infection, testing is not recommended. These infants should receive routine care. 

When pre-and postnatal findings are discrepant (e.g. prenatal diagnosis of microcephaly but normal head size after birth with no other findings consistent with congenital Zika virus infection), clinical judgment is needed. The accuracy of prenatal ultrasound for detection of microcephaly depends on a range of factors (e.g., timing of screening, severity of microcephaly, patient factors). If an infant has no other abnormalities except microcephaly on fetal ultrasound but has a normal physical exam with a normal head (occipitofrontal) circumference after birth, and no other signs of congenital Zika infection, the decision to test the infant would depend on the Zika test results of the mother. If the test results for the mother were negative for Zika virus infection, the infant should receive routine care. If the mother received positive or inconclusive results of tests for Zika virus infection, the infant should be tested for Zika virus infection. If the infant had other findings consistent with congenital Zika virus infection, such as intracranial calcifications or other brain or eye abnormalities, the infant should be tested for Zika virus infection.

Because information on the effects of congenital Zika virus infection is limited, healthcare providers should exercise clinical judgment in the assessment of newborns with abnormalities other than microcephaly, intracranial calcifications, brain and eye abnormalities who were born to mothers with possible Zika virus exposure during pregnancy. For these infants, healthcare providers should consider testing the mother before testing the infant.

For all scenarios, guidelines will be updated as additional information becomes available. Healthcare providers should contact their local, state or territorial health departments to arrange testing.

How are infants diagnosed with possible congenital Zika virus infection?

Zika virus infection can be diagnosed by reverse transcription-polymerase chain reaction (RT-PCR) or through serologic testing. It has not been established which test is most reliable for a diagnosis of congenital infection in newborns. Therefore, both should both be performed. Histopathologic evaluation of the placenta and umbilical cord, immunohistochemical staining on fixed tissue, and Zika virus RT-PCR on fixed and frozen tissue can be performed. Cerebrospinal fluid (CSF) may be tested if obtained for other clinical studies. 

When should an infant or a child be tested for acute Zika virus disease?

Criteria for testing will vary by state. However, acute Zika virus disease should be suspected in an infant or child aged <18 years who 1) traveled to or resided in an area with ongoing transmission of Zika virus within the past 2 weeks or, for an adolescent, who might have been exposed to Zika virus through sexual contact with a male partner who traveled to or resided in an area of active Zika virus transmission, and 2) has ≥2 of the following manifestations: fever, rash, conjunctivitis, or arthralgia. Because transmission of Zika virus from mother to infant during delivery is possible, acute Zika virus disease should also be suspected in an infant during the first 2 weeks of life 1) whose mother, within approximately 2 weeks of delivery, was potentially exposed to Zika virus through travel to or residence in an area of active Zika virus transmission or through sexual transmission, and 2) who has ≥2 of the following manifestations: fever, rash, conjunctivitis, or arthralgia. Healthcare providers should contact their local, state or territorial health departments to arrange testing. Zika virus disease is a nationally notifiable condition.

Arthralgia is a known symptom of Zika virus disease. How might arthralgia manifest in young children?

Arthralgia can be difficult to detect in infants and young children and can manifest as irritability, walking with a limp (for ambulatory children), difficulty moving or refusing to move an extremity, pain on palpation, or pain with active or passive movement of the affected joint.

How is possible acute Zika virus infection confirmed in infants and children?

Acute Zika virus infection can be confirmed by performing reverse transcription-polymerase chain reaction (RT-PCR) on serum within 7 days of symptom onset. Recent reports suggest that Zika virus RNA can be detected in urine for at least 2 weeks after onset of symptoms; therefore, CDC recommends that Zika virus RT-PCR be performed on urine collected <14 days after onset of symptoms in patients with suspected acute Zika virus disease, in conjunction with RT-PCR testing on serum within 7 days after symptom onset. Serologic assays can also be used >4 days after symptom onset to detect Zika virus-specific IgM and neutralizing antibodies. Evaluation of infants and children for acute Zika virus infection should include testing of serum, and may include CSF testing for Zika viral RNA if CSF samples are obtained for other reasons. 

If Zika virus testing of an infant or a child is indicated, how is the test ordered?

Zika virus testing is performed at many state and territorial health departments, and at CDC. Healthcare providers should contact their local, state or territorial health department to facilitate testing. See the Diagnostic Testing webpage for information on how to obtain Zika testing.

What are the challenges in interpreting Zika virus testing in an infant or child?

Zika virus testing in infants and children has several challenges. RT-PCR tests may not detect Zika virus RNA in an infant who had Zika virus infection in utero or a child if the period of viremia has passed. Serologic tests for Zika virus can be falsely positive because of cross-reacting antibodies against related flaviviruses (e.g., dengue and yellow fever viruses). Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies to Zika virus, but neutralizing antibodies may still yield cross-reactive results in infants due to maternal antibodies that were transferred to the infant. It is important to work closely with local, state or territorial health departments to ensure the appropriate test is ordered and interpreted correctly.

Zika Virus Evaluation and Potential Outcomes

What should healthcare providers do to evaluate newborns with positive or inconclusive Zika virus test results?

A thorough physical examination should be performed, including careful measurement of the head (occipitofrontal) circumference, length, weight, and assessment of gestational age. Cranial ultrasound is recommended unless it was performed as part of prenatal screening in the third trimester and clearly showed no abnormalities of the brain. Ophthalmologic evaluation is recommended as well as newborn hearing screen. An evaluation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions is also recommended. Full body photographs and any rash, skin lesions, or dysmorphic features should be documented. If an abnormality is noted, consultation with an appropriate specialist is recommended.

What additional follow-up is recommended for children with microcephaly, intracranial calcifications or abnormal neurologic findings?

Consultations are recommended with a clinical geneticist or dysmorphologist, a pediatric neurologist, and a pediatric infectious disease specialist. A complete blood count including platelet count, and tests for liver enzymes and function should also be conducted. Testing for other congenital infections is also recommended. If any additional anomalies are identified through history, clinical examination, or imaging studies, genetic and other teratogenic causes should be considered.

What long-term follow-up is recommended for infants with positive or inconclusive Zika virus test results?

Repeat hearing screen should be performed at six months of age, as well as follow-up of any hearing abnormalities detected on newborn hearing screening. Continued evaluation of developmental characteristics and milestones, as well as head circumference, is recommended through the first year of life. Appropriate medical specialists (e.g., pediatric neurology, developmental and behavioral pediatrics, physical and speech therapy) should be consulted if any abnormalities are noted and as concerns arise.

If a mother had Zika virus infection during pregnancy but her newborn tests negative for Zika virus, what is recommended for additional follow-up?

In the absence of abnormal findings on examination, the infant should receive routine pediatric care including measurement of growth and development, and appropriate evaluation and follow-up for any clinical findings that arise. If the newborn has abnormal findings on history or examination, diagnostic testing for other causes of the newborn’s conditions should be performed, including testing for other congenital viral infections if indicated.

Is there any information on neurocognitive outcomes in newborns if they are exposed to Zika virus during labor and delivery or after birth?

Perinatal transmission of Zika virus infection has been reported. However, information is limited to rare cases. An asymptomatic case and a symptomatic case (with thrombocytopenia and a diffuse rash) have been reported. Evidence from other flaviviruses, such as West Nile virus and dengue virus, indicate that transmission has resulted in findings in the neonate ranging from no symptoms to severe illness (including fever, thrombocytopenia, hemorrhage, encephalopathy, and adverse neurologic outcomes). The spectrum of clinical features that might be observed in infants who acquire Zika virus during the perinatal period is currently unknown.

What is the prognosis for infants with congenital Zika virus infection?

The prognosis for infants with congenital Zika virus infection is not known.

Are there concerns for long-term complications in older infants and children who are infected with Zika virus?

Information on long-term outcomes among infants and children with acute Zika virus disease is limited. Until more evidence is available to inform recommendations, routine pediatric care is advised for these infants and children. Most children infected with Zika virus are asymptomatic or have mild illness, similar to the findings seen in adults with Zika virus infection. 

Can Zika virus infection cause Guillain-Barré syndrome (GBS) or death in infants or children?

In general, the risk for GBS from any cause appears to increase with increasing age. GBS has been reported following Zika virus infection, although a causal link has not been established. It is unclear how often GBS following Zika virus infection has occurred in children; one report from Brazil refers to 6 patients, aged 2–57 years, with neurologic syndromes (4 with GBS and 2 with acute disseminated encephalomyelitis) after laboratory-confirmed Zika virus infection. Deaths due to Zika virus infection appear to be rare at all ages.

Is there specific treatment for Zika virus infection in infants and children?

Evidence indicates that Zika virus disease in children is usually mild, and treatment is supportive; this includes rest and fluids to prevent dehydration. Non-steroidal anti-inflammatory drugs (NSAIDS) should not be used until dengue is ruled out as a cause of illness and should be avoided in children aged <6 months. Aspirin is not recommended for use with acute viral illnesses due to the risk of Reye’s syndrome. For infants with congenital Zika virus infection, care is focused on diagnosing and managing conditions that are present, monitoring the child’s development over time, and addressing problems as they arise.

Zika Virus Infection and Microcephaly

What is the link between Zika virus and microcephaly?

There is now scientific consensus that Zika virus is a cause of microcephaly— a congenital malformation with smaller than normal head size for age and sex.  It has also been associated with other birth defects and neurologic conditions in children and adults.

If a mother infected with Zika virus near the time of delivery passes the virus to her newborn at birth, can the baby develop microcephaly?

We do not know if a newborn who gets Zika virus infection around the time of birth will develop microcephaly after birth. Babies can develop microcephaly after birth if their head growth slows or fails to develop. There have been no reports of Zika virus infection around the time of birth leading to microcephaly in infants.

What abnormalities have been reported in infants with congenital Zika virus infection?

Congenital Zika virus infection is associated with a wide range of reported brain abnormalities, including but not limited to microcephaly, intracranial calcifications, brain atrophy and asymmetry, abnormally formed or absent brain structures, hydrocephalus, and neuronal migration disorders. Reported neurologic findings include hypertonia, hyperreflexia, irritability, tremors, seizures, brainstem dysfunction, and dysphagia. Reported eye abnormalities include microphthalmia, lens subluxation, cataracts, intraocular calcifications, optic nerve atrophy, optic nerve hypoplasia and pallor, macular pallor, macular chorioretinitis, and chorioretinal atrophy. Other anomalies include excessive and redundant scalp skin, arthrogryposis (congenital joint contractures), and clubfoot.

How is microcephaly diagnosed after birth?

Microcephaly is diagnosed when an infant’s head is smaller than expected as compared to infants of the same age (or gestational age) and sex. For the purpose of evaluating an infant for possible congeni­tal Zika virus infection, microcephaly is defined as occipito­frontal circumference less than the third percentile, based on standard growth charts for sex, age, and gestational age at birth. For a diagnosis of microcephaly to be made, the occipito­frontal circumference should be disproportionately small in comparison with the length of the infant and not explained by other etiologies (e.g., other congenital disorders).

What causes congenital microcephaly?

Causes of congenital microcephaly may include genetic conditions (e.g., chromosomal abnormalities), craniosynostosis, cerebral anoxia, or maternal exposures (e.g., alcohol, mercury, radiation, or severe malnutrition) during pregnancy. Maternal infections that have been associated with microcephaly include cytomegalovirus (CMV), herpes simplex virus, rubella virus, lymphocytic choriomeningitis virus (LCMV), varicella, Treponema pallidum (i.e., syphilis), and Toxoplasma gondii.

What are the potential sequelae of microcephaly?

For infants diagnosed with microcephaly, head size correlates with underlying brain size. However, these measurements do not consistently predict long term sequelae. Neurologic sequelae may include seizures, vision or hearing problems, and developmental disabilities. Symptoms vary with the extent of brain disruption. Additional information about microcephaly is available on CDC’s Microcephaly webpage.

What is the difference between occipitofrontal circumference (OFC) and head circumference (HC)?

Head circumference and occipitofrontal circumference are the same. These terms can be used interchangeably.

When should occipitofrontal circumference (OFC)/head circumference (HC) be measured?

The shape of the head after delivery can affect the accuracy of the OFC/HC measurement as an estimate of brain volume due to molding of the head from the birth canal. The optimal time to measure HC is at 24–36 hours after birth when molding of the head has subsided.

How should occipitofrontal circumference (OFC)/head circumference (HC) be measured?

Head circumference measurements should be taken using a tape measure that cannot be stretched. The tape is securely wrapped around the widest possible circumference of the head, 1–2 finger widths above the eyebrow on the forehead and at the most prominent part of the back of the head. Ideally, the measurement should be taken 3 times and the largest measurement recorded to the nearest 0.1 cm. It may be helpful to have the parent or nurse hold the infant’s arms.

	Image showing a baby with an typical size head, a baby with microcephlay, and a baby with severe micorcephaly

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