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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 has updated its interim guidelines for healthcare providers in the United States caring for infants and children with possible congenital or perinatal Zika virus infection. 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 who has traveled to or resided in an area with ongoing transmission of Zika virus is at risk for Zika virus infection. 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 traveled to or resided in an area with Zika virus transmission within 2 weeks of 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 or around the time of birth. We do not know how often perinatal Zika transmission occurs. Additionally, spread of the virus through sexual contact has been reported. Blood transfusion and organ or tissue transplantation 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 2 weeks of delivery, and the virus passes to the infant at or around the time of delivery. When an infant acquires Zika virus disease 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 RNA has been identified in breast milk, but attempts to culture the virus have been unsuccessful. No evidence of Zika virus infection associated with breastfeeding have been reported. Current evidence suggests that the benefits of breastfeeding outweigh the theoretical risks 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 traveled to or resided in areas affected by Zika virus, testing should be guided by (1) whether the infant has microcephaly or intracranial calcifications detected on prenatal or postnatal ultrasounds and (2) the mother’s Zika virus testing results. 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 or intracranial calcifications who were born to mothers who traveled to or resided in an area with active Zika virus transmission during pregnancy. For these infants, healthcare providers should consider testing the mother before testing the infant. Healthcare providers should notify their local, state or territorial health departments to arrange testing.

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

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 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 traveled to or resided in an affected area within 2 weeks of delivery and 2) who has ≥2 of the following manifestations: fever, rash, conjunctivitis, or arthralgia. Healthcare providers should notify their local, state or territorial health departments to arrange testing. As an arboviral disease, 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 in 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.

When should an infant with microcephaly or intracranial calcifications be tested for Zika virus?

For infants with microcephaly or intracranial calcifications and whose mothers have a history of travel to or who reside in areas with ongoing transmission of Zika virus, Zika virus testing is recommended within 48 hours of birth, if possible. Healthcare providers should work with their local, state or territorial health departments to arrange testing.

When should an infant with possible congenital infection and no evidence of microcephaly or intracranial calcifications be tested for Zika virus?

For infants without evidence of microcephaly or intracranial calcifications, Zika virus testing is recommended under the following circumstances: (1) if the mother tested positive (e.g. RT-PCR, IgM) for Zika virus, or (2) if the mother had inconclusive Zika virus test results. For infants without evidence of microcephaly or intracranial calcifications and whose mothers either tested negative for Zika virus or were not tested for Zika virus, testing is not recommended. The infant should receive routine care.

How should infants born to mothers who traveled to or resided in an area with Zika virus transmission be evaluated if the mother was not tested for Zika virus infection during pregnancy?

For infants born to mothers who were potentially exposed to Zika virus, the results of previous prenatal ultrasounds and maternal Zika virus testing should be reviewed and a thorough newborn physical examination, with careful measurement of head (occipitofrontal) circumference, length, and weight, should be performed. Infants without evidence of microcephaly or intracranial calcifications whose mothers have negative Zika virus test results or who were not tested for Zika virus should receive routine care. 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 or intracranial calcifications who were born to mothers who traveled to or resided in an area with active Zika virus transmission during pregnancy. For these infants, healthcare providers should consider testing the mother before testing the infant.

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 the detection of Zika virus-specific IgM and neutralizing antibodies. It has not been established which test is most reliable for a diagnosis of congenital infection in newborns. Therefore RT-PCR and IgM tests should both be performed. Plaque-reduction neutralization testing (PRNT) may also need to be performed to measure virus-specific neutralizing antibodies to differentiate Zika virus from infection with or vaccination for other flaviviruses. 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.

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

Zika virus infection can be confirmed by performing reverse transcriptase-polymerase chain reaction (RT-PCR) on serum within 7 days of symptoms onset. Serologic assays can also be used to detect Zika virus-specific IgM and neutralizing antibodies 4 or more days after symptoms onset. Evaluation of infants and children for acute Zika virus infection should include testing of serum and may include cerebrospinal fluid (CSF) testing for Zika viral RNA, if samples were obtained as part of routine care.  A CSF sample collected for the sole purpose of Zika RT-PCR testing is not recommended.

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

There are no commercially available tests for Zika virus. Zika virus testing is performed at the CDC Arbovirus Diagnostic Laboratory and at some state and territorial health departments. 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.

When is an infant or child considered to have laboratory evidence of Zika virus infection?

Laboratory evidence of Zika virus infection in an infant or child would include, in any clinical specimen, detectable Zika virus in culture, Zika virus RNA  (by RT-PCR) or antigen, or a clinical specimen positive for Zika virus IgM with confirmatory neutralizing antibody titers ≥4-fold higher than dengue virus neutralizing antibody titers. If Zika virus antibody titers are <4-fold higher than dengue virus antibody titers, test results for Zika virus would be considered inconclusive.

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 or child who had Zika virus infection in utero 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 Prevention for Infants and Children

What preventive measures should be taken to avoid Zika virus infection in infants and children?

All individuals in areas of ongoing transmission of Zika virus should take measures to prevent mosquito bites to avoid infection with Zika virus, as well as other mosquito-borne illnesses such as dengue and chikungunya. Mosquito-bite prevention includes using air conditioning or window and door screens when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear, and using insect repellents. When used as directed on the product label, most Environmental Protection Agency (EPA)-registered insect repellents can be used to protect children aged ≥2 months against mosquito bites. Products containing oil of lemon eucalyptus should not be used on children under the age of three years. Mosquito netting can be used to cover infants in carriers, strollers or cribs to protect them from mosquito bites.

Can insect repellents be used on children aged 2 months or older?

Yes. When used as directed by the product label, most EPA-registered insect repellents can be used on children aged 2 months or older. Products containing oil of lemon eucalyptus should not be used on children under the age of three years. However, children should not be allowed to handle or spray the repellent. Caretakers should apply repellent to their own hands first and then put it on the child. They should also avoid applying repellent to cut or irritated skin and children’s hands because children frequently put their hands in their eyes and mouths. The EPA does not recommend any additional precautions for using registered repellents on children other than those listed above.

Visit this page for more information on the use and safety of insect repellents.

How can infants aged less than 2 months be protected against mosquito bites?

Insect repellent should not be used on infants younger than 2 months of age. Therefore, mosquito netting can be used to cover infants in carriers, strollers or cribs to protect them from mosquito bites.

Zika Virus Evaluation and Potential Outcomes

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

A thorough physical examination should be performed, including careful measurement of the head 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 congenital anomalies are identified through clinical examination and imaging studies, genetic and other teratogenic causes should be considered.

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 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 neonates 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 two cases: one of these infants was asymptomatic and the other had thrombocytopenia and a diffuse rash. 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, and hemorrhage). 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 a newborn 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. Thus, 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-Barre 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; no further data are available. Deaths due to Zika virus infection appear to be very 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 in Brazil and the high numbers of infants born there with microcephaly?

Zika virus infections have been confirmed in several infants with microcephaly from Brazil. The time frame and geographic location of reports of infants with microcephaly coincides with the outbreak of Zika virus infections in Brazil. After careful review of existing evidence, and using two sets of accepted scientific criteria, scientists at CDC have concluded that Zika virus is a cause of microcephaly and other severe fetal brain defects.

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 at birth will develop microcephaly after birth. Babies can develop microcephaly after birth if their head growth slows or fails to develop after birth. There have been no reports of Zika virus infection around the time of birth leading to microcephaly in infants.

What birth defects have been reported in infants with confirmed congenital Zika virus infection?

Brain abnormalities reported in infants with microcephaly and laboratory-confirmed congenital Zika infection include microcephaly and disrupted brain growth.

What birth defects have been reported in infants with suspected congenital Zika virus infection?

A report of 35 infants with microcephaly who were born during an outbreak of Zika virus infection in Brazil in 2015 described the following brain abnormalities: intracranial calcifications, ventriculomegaly, and neuronal migration disorders (lissencephaly and pachygyria). Other anomalies included congenital contractures and clubfoot. Some infants with possible Zika virus infection have been found to have intracranial calcifications and abnormal eye findings. An important distinction is that neither these infants nor their mothers had laboratory-confirmed Zika virus; however, 75% of mothers reported symptoms consistent with Zika virus.

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 (e.g., Fenton, Olsen, CDC, or WHO growth curves) 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 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. The OFC should be measured three times and the largest value should be used.

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

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 causes congenital microcephaly?

Recently, CDC concluded that Zika virus infection during pregnancy is a cause of microcephaly and other severe fetal brain defects. Other causes of congenital microcephaly may include genetic conditions such as chromosomal abnormalities or maternal exposures (e.g., alcohol, mercury, or radiation) during pregnancy. Maternal infections that have been associated with microcephaly include cytomegalovirus (CMV), herpes simplex virus, rubella virus, lymphocytic choriomeningitis virus (LCMV), Treponema pallidum (i.e., syphilis), and Toxoplasma gondii.

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