Recommendations on the Prevention and Treatment of Zika Virus for Canadian health care professionals

An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)

Table of contents

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Abstract

Background: Zika virus (ZIKV) has recently emerged as a disease of significant public health concern. ZIKV infection can cause microcephaly and other congenital abnormalities as well as neurologic complications such as Guillain-Barré syndrome.

Objective: To summarize current evidence related to ZIKV and to provide guidance to health care professionals on infection prevention and patient disease management. The main patient population targeted by our recommendations are Canadians travelling to or returning from ZIKV affected areas, as well as their partners.

Methods: This Statement was developed by a working group of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Recommendations are based on a literature review and clinical judgment.

Results: While in affected areas travellers should use personal protective measures against mosquito bites including insect repellents and protection of living areas against mosquito entry. Pregnant women should avoid travel to areas designated by the World Health OrganizationFootnote 1 (areas outside the United States (US)) or the Centres for Disease Control and PreventionFootnote 2 (areas within the US) as being of concern because of ongoing ZIKV transmission. Women planning a pregnancy should consult with their health care provider and consider postponing travel to these areas. Other travellers may wish to consider deferring travel to designated areas based on their values, and preferences.

Sexual transmission of ZIKV occurs. For this reason, conception should be avoided for couples while in risk areas and after return (see recommendation table for details). Couples should practice abstinence or use barrier methods (e.g. condoms) for the duration of a pregnancy in the case of a current pregnancy and a male who is or has been in a risk area.

Health care providers should take a travel history from their pregnant patients including relevant information related to the travel history of their partner(s). Screening and management recommendations are provided for all affected/implicated persons, including: potentially contagious partners, pregnant women (symptomatic and asymptomatic), and the fetus or infant of potentially infected women. There is no specific therapy for the treatment of ZIKV infection.

Conclusion: Infection with ZIKV can have serious consequences. Prevention relies on: avoiding primary infection by preventing mosquitoes bites; and, by reducing the risk of secondary transmission through prevention of sexual transmission. CATMAT will continue to monitor and review new evidence related to ZIKV, and will update these recommendations accordingly.

Introduction

Zika virus (ZIKV) infection is caused by a flavivirus transmitted through the bite of an infected Aedes mosquito, mainly Aedes aegypti. Aedes albopictus has also been associated with transmission of ZIKVFootnote 3. Although infections in humans were documented in the 1950s, ZIKV has only recently emerged as a disease of significant public health concern. Currently, there is a large outbreak underway in the Americas with transmission also occurring in some other countries. Outbreaks have also recently occurred on islands in the South Pacific, Singapore, and in Cabo Verde. Before this, known areas of endemic transmission were limited to Asia and Africa. Transmission intensity in these areas was thought to be low, although surveillance has been limited. It is likely that the virus will continue to spread because the mosquito vectors are found in many tropical and subtropical regions as well as in some warmer temperate areasFootnote 4,Footnote 5.

A major concern with the current outbreak is the spatial and temporal clustering of ZIKV activity with an increase in the incidence of children born with microcephaly, defined as a head circumference measurement below the third percentile and disproportionate to the weight and length percentile measurementsFootnote 6,Footnote 7. For example, an epidemiologic study demonstrated a strong association of ZIKV and microcephaly in the population of French Polynesia, where an outbreak took place from 2013-2015Footnote 8. The role of ZIKV in microcephaly is further supported by detection of ZIKV viral genome in amniotic fluid, placenta and tissues of affected fetuses and neonatesFootnote 9,Footnote 10. The pattern of microcephaly associated with ZIKV appears to be within the context of a broader constellation of fetal anomalies now referred to as congenital Zika syndrome (CZS), a syndrome that may be distinct from that caused by other types of fetal insultsFootnote 9. A causal relationship between prenatal ZIKV infection and infant microcephaly or other severe neurologic abnormalities has been acknowledged in the scientific community based on the available evidenceFootnote 11,Footnote 12,Footnote 13,Footnote 14.

Although disease is usually mild in adults, ZIKV infection can cause neurologic sequelae such as Guillain-Barré syndrome (GBS) Footnote 7,Footnote 15. A recent case control study done in French Polynesia estimates a 0.24 in 1000 risk for developing GBS in persons infected with ZIKV. This is comparable to the risk of 0.25 to 0.65/1000 observed following Campylobacter jejuni infection. There are also reports of acute disseminated encephalomyelitis (ADEM) following ZIKV infectionFootnote 16.

Finally, there are multiple reports of sexual transmission of ZIKV from infected persons to their partner(s).  While most reports of sexual transmission have been from male-to-female, female-to-maleFootnote 17 and male-to-maleFootnote 18,Footnote 19,Footnote 20,Footnote 21,Footnote 22, transmission also has been reported.

The purposes of this statement are to review current knowledge related to ZIKV infection and to provide guidelines for health care providers on prevention and management of ZIKV disease.

Methods

This statement was developed by a working group of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Members of the working group were from CATMAT, the Public Health Agency of Canada (the Agency) and the Society of Obstetricians and Gynaecologists of Canada. Each member was a volunteer, and none declared a relevant conflict of interest. This guideline complements existing CATMAT statements including the Statement on Personal Protective Measures to Prevent Arthropod bitesFootnote 23 and the Statement on Pregnancy and TravelFootnote 24. A literature search for evidence related to ZIKV was conducted. Guidelines and reports from international and national public health organizations including, but not limited to, the Centers for Disease Control in the United States, the Pan American Health Organization and the World Health Organization, were also retrieved and reviewed.

Epidemiology

ZIKV was first isolated from monkeys in Uganda in 1947. Soon after (1952), human infections were detected in Uganda and TanzaniaFootnote 25,Footnote 26. However, human infections were rarely reported until 2007, when the first major outbreak of ZIKV disease occurred on the island of Yap (Micronesia) in the southwestern Pacific OceanFootnote 27. Between 2013 and 2015, additional outbreaks occurred on islands and archipelagos from the Pacific region including a large outbreak in French PolynesiaFootnote 28,Footnote 29 and another in Cabo VerdeFootnote 30. In 2014, local transmission in the Americas was reported for the first time on Easter IslandFootnote 31.  ZIKV has since spread to a wide region of the AmericasFootnote 32 and to several other regions. It is anticipated that ZIKV will continue to spread, particularly in tropical and subtropical regionsFootnote 33,Footnote 34.

Transmission

The mosquitoes associated with ZIKV can be active during the day and night, with biting activity often peaking in the morning and later in the afternoon. In vertebrate hosts, the incubation period is usually three to 12 days, with blood viremia (the period when ZIKV is present in the blood) usually lasting for three to five daysFootnote 35,Footnote 36,Footnote 37. Viremia has typically been detected only during symptoms or for a few days thereafter, although cases of prolonged viremia have been reported during pregnancyFootnote 38, in an adult maleFootnote 39 and in a newbornFootnote 40. It is uncertain whether viremia is detectable prior to symptoms, or during asymptomatic infection. If bitten by a competent mosquito while viremic, the human (or other) host can infect the mosquito thereby completing the transmission cycleFootnote 34. Vertical transmission between mother and developing fetus also presumably occurs during this viremic periodFootnote 41,Footnote 42. Other described routes of transmission include blood product transfusion Footnote 43 and sexual transmission from men after symptomatic infectionFootnote 18,Footnote 19,Footnote 20,Footnote 21.  There is a single report of sexual transmission from a symptomatic infected woman to a sexual partnerFootnote 17 and another report of sexual transmission from an asymptomatically infected male to their partnerFootnote 44. There is insufficient evidence to evaluate the quantitative risk associated with the various forms of sexual transmission at this time. There has also been a report of household transmission, without a clear mechanism, raising the question of transmission by some other form(s) of contactFootnote 45.

Viral RNA has been detected in the semen of males previously known to have symptomatic disease. The average duration of shedding in semen is unknown but there is one report of detection of RNA 6 months after symptoms of acute illnessFootnote 46. Viral RNA has also been detected in salivaFootnote 29, urineFootnote 47,Footnote 48 and in cervical mucousFootnote 49,Footnote 50 more than a week after clearance of blood viremia. Neutralizing antibodies for ZIKV are detectable after infection, and by extrapolation from other flaviviruses, post-infection immunity is presumed to be long lasting.

ZIKV RNA has been detected in breast milk; however, there have not been any documented reports of transmission to infants through breastfeedingFootnote 19. No complications specifically related to infection during the newborn period have been described, however data are very limited. At this time, the World Health Organization (WHO) considers that “the benefits of breastfeeding for the infant and mother outweigh any potential risk of Zika virus transmission through breast milk”Footnote 51. Until further evidence is available regarding transmission through breast milk, CATMAT suggests that potential benefits and harms of breastfeeding during acute ZIKV infection should be discussed with each patient, and decisions be made on an individual basis.

Clinical Manifestations

Approximately 20-25% of persons infected with ZIKV will manifest symptoms, including fever, myalgia, pruritis, eye pain, and maculopapular rashFootnote 27,Footnote 52. Early clinical manifestations are similar to other arboviral infections including dengue and chikungunyaFootnote 52,Footnote 53. Thus, the differential diagnosis of a febrile returned traveller from the Americas will likely include these arboviral infections, as well as malariaFootnote 54 and other viral illnessesFootnote 55,Footnote 56.

Post-infectious neurologic complications, such as GBS, have been reported from many of the countries affected by the current ZIKV outbreakFootnote 15,Footnote 36,Footnote 57,Footnote 58. They include French Polynesia where a case-control study estimated that the odds of positive ZIKV serology was substantially greater in GBS cases compared to matched controls (OR 59.7; 95% CI 10.4 to ∞)Footnote 59. In the same study, and based on a ZIKV population seroprevalence of 0.66, the risk of GBS following ZIKV infection was estimated at approximately 0.25/ 1000. Other neurological manifestations have also been reported in association with ZIKV infection, e.g., acute myelitis, meningoencephalitis, and acute disseminated encephalomyelitisFootnote 16,Footnote 60,Footnote 61, suggesting that the neurological spectrum of sequelae associated with ZIKV may be broader than previously thought.

Clinically relevant thrombocytopenia and subcutaneous hematomas have been reported in a small number of casesFootnote 62,Footnote 63. Deaths from other causes have also been reportedFootnote 64,Footnote 65.

Brazil, French Polynesia and several other affected countries (e.g., Colombia)Footnote 7 have reported CZS.  Common manifestations include microcephaly, cerebral atrophy, abnormal cortical development, callosal hypoplasia, and diffuse subcortical calcificationsFootnote 12,Footnote 69. Ocular abnormalities and other congenital malformations such as arthrogryposis and hydrops fetalis have also been describedFootnote 66,Footnote 67,Footnote 68.  

Although the likelihood of serious fetal harm following infection is unknown there is evidence to suggest that it is not a rare occurrence. For example, a case series from Brazil suggests that infection is associated with serious outcomes including fetal death, placental insufficiency, fetal growth restriction, and central nervous system (CNS) injury (12/42 ZIKV-infected females on whom Doppler ultrasonography was performed)Footnote 70. A retrospective study of patients in French Polynesia suggested that the impact of ZIKV was primarily through infections occurring during the first trimester (when it was estimated to result in an approximately 1% risk of microcephaly)Footnote 8.

Reviews of the epidemiology of ZIKV, as well as the causal association of ZIKV and microcephaly have been recently publishedFootnote 11.

Risk to travellers

The Agency has published an assessment of the risk of ZIKV to CanadiansFootnote 71. It concludes:

  • For most infected travellers, ZIKV will have little or no health impact (Low impact, with medium confidence). However, severe outcomes (e.g., GBS) might occur in some affected individuals (High impact, high confidence).
  • There could be Very High impact (with high confidence) to the unborn children of women who become infected with ZIKV while pregnant.
  • Sexual transmission, from symptomatic male travellers to a sexual partner who has not travelled, has been reported. As relatively few travellers will be infected with ZIKV, the likelihood of transmission via this route is Low (medium confidence). This changes if a man does become infected and is symptomatic with ZIKV, the likelihood of transmission to his sexual partner is assessed as Medium (low confidence).

This assessment also considered factors that might affect the likelihood or impact of ZIKV infection. While evidence is very limited in this regard, several plausible relationships were identified:

  • Conditions at higher elevations (≥ 2,000 m) are generally not supportive of viral replication in, or survival of, Aedes aegypti populations. Correspondingly, the relative likelihood of infection with ZIKV might be substantially lower for travellers (depending on how much time they spend at higher compared to lower elevations) to such areas.
  • All else held equal, the likelihood of infection is higher in countries/areas that are reporting high levels of ZIKV activity compared to those that are not.
  • The likelihood of infection is likely lower for shorter travel durations and/or when staying in protected environments (e.g., well screened and air-conditioned accommodations, transiting through an airport in a risk area). This might also apply to situations where the traveller is staying in an isolated location, i.e. where there are relatively few residents who might support sustained transmission.

CATMAT stresses that, at this time, robust quantitative assessments for the full spectrum of ZIKV-associated risks are not possible. This reflects, among other things, uncertainties related to: the likelihood that travellers will be infected with ZIKV, the likelihood that travellers infected with ZIKV will manifest serious sequelae like GBS, and the probability that maternal infection during pregnancy will lead to fetal infection. Given this uncertainty, as well as the potentially severe effects of ZIKV infection on the fetus, our recommendations are conservative. However, we also realize that there might be circumstances where a patient is unable to or unsure about whether to adhere to our guidance. In this situation, we believe it is appropriate to consider factors such as those identified above to help inform the decision-making process (also see below, decision to travel to risk areas).

Areas of risk

There is widespread transmission of Zika virus over much of South and Central America, the Caribbean, but not temperate areas of Argentina and Chile. Local transmission is also being reported in limited region of the state of Florida and a number of countries in Southeast Asia and the Western Pacific Region.

The areas of risk where the recommendations in this statement apply can be found at the following sources:

  • Countries (excluding the United States) with a reported outbreak from 2015 onward (Category 1) and those with possible endemic transmission or evidence of local mosquito-borne Zika infection in 2016 (Category 2) are updated weekly by the World Health Organization in the Zika Situation report Footnote 1.
  • The Centers for Disease Control and Prevention maintains a map of the area of risk (currently limited to the state of Florida) where local mosquito born transmission has been identifiedFootnote 2.

There are areas of Africa and Asia where ZIKV transmission has previously occurred, or is considered endemic with very low potential for transmission to travellers. These are not currently designated as risk areas by the Agency, nor are countries/territories where ZIKV has been reported, but only in travellers and/or as a result of sexual transmission.

Prevention - Decision to travel to areas of risk

All travellers

Health care providers should discuss with travellers what is known and what is not known about ZIKV to help their patients make an informed choice about travel based on this guideline and the ZIKV information on the Government of Canada’s ZIKV webpageFootnote 72. Factors to consider include:

  • The possibility of serious sequelae such as post-infection neurologic complications (e.g., GBS, ADEM).
  • The potential for ZIKV infection during pregnancy to have a severe impact of the fetus.
  • The potential for sexual transmission from men to their sexual partners, which is particularly relevant to couples who are actively trying to conceive.
  • The potential for co-morbidities to predispose to more serious outcomes (there is little specific evidence in this regard, though it is reasonable to expect such impacts).
  • Patients’ values and preferences (including risk perception and risk tolerance).
  • The potential impacts of following the recommendation on a couple’s reproductive plans.
  • The large uncertainties that continue to hamper the development of robust risk assessments for Canadians.
  • Itinerary- specific factors (see section on risk to Canadian travellers) that might affect the likelihood of being exposed to ZIKV.

Pregnant women and women who are planning a pregnancy

CATMAT recommends that pregnant women avoid travel to areas of risk listed in the above sources. Women planning a pregnancy should consult with their health care provider and consider postponing travel to areas of risk as defined above. Pregnant women and those planning a pregnancy who travel to a risk area are strongly advised to use Personal Protective Measures (PPM) against insect bites (see below for more detail). As for travellers generally (see previous section), health care providers should help their patients make an informed decision regarding travel or other aspects of ZIKV prevention. The risk of severe adverse outcomes of pregnancy deserves particular emphasis.

Prevention of mosquito-borne transmission

CATMAT recommends that all travellers to areas of risk should be advised to strictly adhere to recommendations for the use of personal protective measures against mosquito bites (see below). Because the mosquitoes that transmit ZIKV can bite at any time (including during daylight hours), PPM should be used through all hours of the day and night. In addition to ZIKV, PPM provide protection against other vector-associated diseases such as malaria, dengue, and chikungunya. Recommendations for PPM can be found in CATMAT’s Statement on Personal Protective Measures to Prevent Arthropod BitesFootnote 23. These are summarized below:

Personal protective measures to prevent arthropod bites

  1. Cover up:
    • Wear light-coloured, long-sleeved, loose fitting, tucked-in shirts, long pants, shoes or boots (not sandals), and a hat.
  2. Use insect repellent on exposed skin:
    • It is recommended that adults use repellents that contain DEET (20-30%) or icaridin (20%).
    • It is recommended that children six months to twelve years of age use repellents that contain icaridin (20%). As a second choice, this age group can use repellents with age-appropriate DEET or p-Menthane-3,8-diol concentrations as per label.
    • If bites cannot be avoided using a physical barrier, consider use of up to 10% DEET or 10% icaridin for infants under six months of age.
  3. Protect living areas from mosquito entry:
    • Stay in a well-screened or completely enclosed air-conditioned room.
    • Reduce your risk in work and accommodation areas by closing eaves, eliminating holes in roofs and walls and closing any other gaps.
  4. If mosquito entry into living quarters cannot be otherwise prevented (e.g. by screening):
    • Use a bed net (e.g. for sleeping or resting inside), preferably treated with insecticide.
    • Netting can also be used to protect children in playpens, cribs, or strollers.
    • Bed nets will also provide protection against diseases like malaria.
  5. Apply a permethrin insecticide to clothing and other travel gear for greater protection:
    • Although permethrin clothing treatments are not widely available in Canada, travel health clinics can advise you how to purchase permethrin and pre-treated gear before or during your trip.
    • Permethrin-treated clothing is effective through several washes.
    • Always follow label instructions when using permethrin.
    • Do not use permethrin directly on skin.

Insect repellents, insecticide treated bed nets and permethrin treated clothing/clothing treatments have been reviewed for safety in Canada and/or the United States. They are considered safe, including for children, pregnant and breastfeeding women if used in accordance with label directions.

Prevention of sexual transmission

ZIKV RNA has been detected in semen as long a 6 months after acute illnessFootnote 21,Footnote 46,Footnote 73. It is not known how long viral shedding in semen can last, how often this might happen when infection is asymptomatic, or how easily virus can be transmitted by sexual contact. The number of reports of sexual transmission has been increasing, suggesting this may not be a rare occurrence. When properly used, condoms should minimize the risk of sexual transmission.

Pregnant women and their partner

While in a risk area, pregnant women and male partners should practise abstinence or use condoms. If a male partner has been in a risk area, couples should practise abstinence or use barrier methods (e.g. condoms) for the duration of the pregnancy. Although the exact mechanisms of sexual transmission from females to a partner are uncertain, contact with female genital secretions may also present a risk to pregnant womenFootnote 17. If the partner of a pregnant female has been in a risk area the couple should practice abstinence or use condoms for the full duration of the pregnancy (including after return).

Couples planning a pregnancy

Based on current information on the incubation period and duration of viremia, and the unclear duration of viral persistence in tissues, women planning a pregnancy should wait at least two months after their return from an area of risk before trying to conceive. For couples where the male partner has travelled in an area of risk, it is reasonable to delay trying to conceive for six months. Based on current evidence, transmission after six months, if it occurs, is likely a very rare occurrence. Any decision to extend the period of abstinence or use of barrier precautions beyond this time should be in accord with the individual patient's values and preferences.

Couples outside the context of current or planned pregnancy

Men who have returned from a risk area and who wish to reduce the possibility of sexual transmission to their partner (outside of the context of pregnancy) can do so through appropriate use of condoms. Use of condoms likely provides the greatest protection in the first weeks following illness, but given the potential for long-term persistence in semen, condom use should be considered for six months after return from a risk area.

There is a report of sexual transmission from female to maleFootnote 17. It is possible that this event resulted from contact with viraemic blood. Condom use or use of other barrier methods likely reduces the risk of such transmission, and is reasonable for a period of two months after symptomatic disease, or after return from an endemic area in the case of an asymptomatic female. Caution should be used to avoid direct contact with menstrual blood.

Role of laboratory testing in transmission prevention or monitoring of pregnant women

Laboratory testing for ZIKV infection is fully described below. In theory, based on information from other similar viral infections, the absence of ZIKV-specific antibodies two weeks or more after the last possible exposure implies that the individual has never been infected, and is not contagious to sexual partners or to the fetus. Depending on the context, such seronegative individuals could consider discontinuing measures to intensively follow the pregnancy for ZIKV-related complications, as well as measures to prevent sexual transmission (for specific recommendations see table). The absence of ZIKV RNA in a semen sample might indicate absence of contagiousness at that time, but there are no data to support the use of this approach, and there remains the theoretical risk of poor test sensitivity for some ZIKV strains. Currently, testing in Canada is focussed on symptomatic individuals and pregnant women. Testing of asymptomatic individuals (men or non-pregnant women) is not routinely offered though there may be circumstances where it can be made available (see below).

Laboratory Diagnosis

Molecular testing using reverse-transcriptase PCR (RT-PCR) is conducted by some provincial laboratories in Canada. The National Microbiology Laboratory (NML) provides support to provinces and territories, along with confirmatory testing. Sensitivity and specificity of molecular tests are unknown, but presumed to be high, at least in the initial few days of illness, since ZIKV appears to circulate in the blood for the first three to five days after onset of symptomsFootnote 33. ZIKV RNA may be present in urine for a few days after it is no longer detectable in bloodFootnote 33,Footnote 74. Information about NML’s guidelines and testing recommendations are available on the Government of Canada’s websiteFootnote 75.

At the NML, serologic testing is currently performed using a CDC based in-house IgM enzyme linked immunosorbent assay (ELISA) followed by a confirmatory ZIKV plaque reduction neutralization test (PRNT)Footnote 36. Antibodies appear approximately five to six days after onset of symptomsFootnote 36. For the acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity. For the convalescent patient with symptom onset over 10 days ago, only serology should be requested. Appropriate diagnostic specimens for RT-PCR testing include plasma/serum, urine, cerebrospinal fluid (CSF), amniotic fluid and placental tissue. Serology is usually only performed on serum; however, viral antibodies may be detected in CSF in some cases of neurological disease.

As ZIKV is a member of the flaviviridae, serologic tests, including the IgM ELISA, may be cross-reactive with other flaviviruses such as dengue, West Nile, and Yellow Fever (including among vaccine recipients)Footnote 4. Confirmation of ZIKV therefore rests on amplification of viral RNA by RT-PCR, or by confirmatory PRNT serologic testing. Confirmatory testing generally requires neutralizing IgG production, which may appear later than IgM. The specificity of the IgM ELISA is limited particularly during secondary flavivirus infections. Patients whose serum samples are IgM positive and have ZIKV-specific antibodies confirmed through PRNT are confirmed cases of viral infection. However, it is also recommended for equivocal cases that acute and convalescent sera be collected 2-3 weeks apart to document a seroconversion or a diagnostic increase (four-fold or greater) in virus specific neutralizing antibodies. This is because individuals previously infected with or vaccinated against flaviviruses may exhibit cross reactivity in PRNT tests making them difficult to interpret. As discussed above, a negative serology at least two weeks after the last possible exposure is presumed to indicate the absence of recent infection, although the precise sensitivity of currently available tests has not been determined. If a negative serological test result is being considered in order to support the discontinuation of transmission precautions, a careful risk assessment is required.

PCR for ZIKV can be performed on amniotic fluid (when amniocentesis is technically feasible) to confirm infection of the fetus. At this time, the risk of adverse outcomes of pregnancy if the fetus is infected with ZIKV is unknown, so the risk of the procedure must be weighed against the clinical utility of this test result. A negative PCR result likely means that the fetus is not currently infected, but would not eliminate the possibility of previous infection. It is not known when ZIKV RNA would be expected to appear in amniotic fluid after infection, or how long it is likely to be detectable. There is some evidence that viral RNA may persist in amniotic fluid for monthsFootnote 76.

For postnatal diagnosis of congenital infection, PCR for ZIKV can be performed on placental tissue, umbilical cord blood or infant blood, and CSF for confirmation of congenital infection. It is possible, however, that infants or fetuses infected weeks prior to specimen sampling will no longer have detectable viral RNA.

Screening and Management

Evaluation of non-pregnant travellers returning from endemic countries

Testing for ZIKV infection (PCR) should be considered in the diagnosis of any ill traveller with compatible epidemiologic and clinical history, when symptom onset is within three days after arrival in, to 14 days after departing from an area of risk. Testing for other similar viral infections and for malaria should also be done as appropriate.

Serologic testing should be considered for male returned travellers whose clinically compatible illness has resolved, and are at least two weeks post exposure, in order to assess for potential contagiousness to sexual partners.

Serological testing of male individuals with a history of travel to an area with Zika virus transmission but no history of related symptoms will be considered if their partners plan on becoming pregnant within 6 months of travel to an affected area. Samples should be collected at least two weeks after return and follow up serology several weeks later is advised due to possible variations in immune response to viral infection.

A negative test result for a symptomatic or asymptomatic patient, whether from an initial or follow-up serology (e.g., if the first test is equivocal), indicates that a recent ZIKV infection is very unlikely.  In this situation, and outside the context of a current pregnancy, patients (and their partners) might consider forgoing recommendations related to preventing sexual transmission of ZIKV. This decision should be made in consultation with a health care provider, and should be set against the broader context of the likelihood of infection and patient values and preferences. Use of barrier protection during the testing period is highly recommended.

Additionally, pre-conceptual testing of male or female individuals with a history of travel to an area with ZIKV transmission but no history of related symptoms will be considered on a case-by-case basis by the NML if conception cannot be delayed for medical reasons. In this circumstance, it is recommended that test results be used as described above. It may be necessary to discuss these cases with your local or provincial laboratory before ordering the test.

Testing an asymptomatic individual simply out of curiosity concerning their serostatus would not be a prudent use of limited resources. Given that neurologic disorders like GBS have occurred following ZIKV infection, returning travellers should be counselled to report any neurologic symptoms to their doctor. In the event of the diagnosis of GBS or other unusual neurologic syndrome, a travel history for the patient and any male sexual partners should be elicited. If ZIKV infection is thought to be potentially associated with the illness, a specialist should be consulted.

Evaluation in the context of pregnancy

Evaluation of pregnant women with a travel history to an area of risk

Health care providers should take a travel history from their pregnant patients including relevant information related to the travel history of their partner(s). Any patient who indicates that they or their partner have recently travelled to an area of risk should be further evaluated.

Screening of asymptomatic pregnant women is recommended and should be discussed on a case-by-case basis between the woman and her health care provider. Screening would consist of serology at least two weeks after the last potential exposure, as well as fetal ultrasounds, at a frequency to be determined in consultation with the woman’s obstetrician, at least until serology is shown to be negative. The usefulness of serology will depend partly on the turn-around time for results, which can be discussed with the local laboratory. The decision to test should include consideration of how the results of the screening tests would be used to inform subsequent decisions. Diagnosis and identification of poor fetal outcomes will allow for appropriate counselling.

Pregnant women and their partners may be justifiably concerned about the risk of ZIKV infection to their fetus and may want to receive counselling to decide the best course of action, including the question of termination. The risk of vertical infection (with clinical sequelae) in the setting of symptomatic or asymptomatic maternal infection in a given trimester of pregnancy is unknown, but appears highest in the first trimesterFootnote 8. However severe sequelae have been reported after infection at all stages of pregnancyFootnote 70. This uncertainty makes pregnancy counselling a difficult prospect. Regardless, discussion and informed decision making regarding options for management of ZIKV infection in pregnancy (much like any other congenital infection or congenital anomaly) requires thorough consultation with a Maternal Fetal Medicine Specialist or another specialist familiar with reproductive infectious diseases. As understanding of the risks of ZIKV infection in pregnancy becomes clearer, so too will the related counselling messages, which in turn will allow each patient to make her own individual decision about her pregnancy.

Evaluation of pregnant women with symptoms compatible with ZIKV infection

Testing (including PCR) should be offered to pregnant women with acute signs and symptoms compatible with ZIKV. As described above, for the acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity. For the convalescent patient with symptom onset over 10 days ago, only serology should be requested. Repeated ultrasound monitoring is indicated, unless the woman is found to be negative on laboratory testing. A woman whose fetus is suspected of having a congenital anomaly should also be offered testing if she or her partner has travelled to any location where ZIKV transmission may be occurringFootnote 1Footnote 2 even at a low level.

The risk of microcephaly or other adverse pregnancy outcomes for a woman known to be infected with ZIKV cannot be estimated from currently available data. Although measurements of head circumference and biparietal diameter may occur as early as 15 weeks, there is no defined gestational age by which microcephaly can be ruled out. Serial monitoring by ultrasound with close attention to measurement trends over time is recommended. It is possible that changes in intracranial anatomy may not be elucidated until well into the third trimester, or later.

Evaluation of the fetus among pregnant women diagnosed with ZIKV infection

Serial ultrasounds (every 3-4 weeks) are recommended in pregnant women with confirmed or suspected (if testing results are pending) ZIKV infection in pregnancy, and for asymptomatic pregnant travellers returning from areas of risk while awaiting diagnosis, to help define risk and counsel the mother. Should CNS calcifications or fetal microcephaly be noted at ultrasonography of the asymptomatic pregnant returned traveller, then specific ZIKV testing of the fetus (e.g., amniocentesis), in addition to other investigations to elucidate alternate aetiologies, should be considered to help define the likely cause of the anomaly.

Evaluation of the infant born to a woman diagnosed with ZIKV infection or with suspected congenital ZIKV infection or CZS

Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central nervous system abnormalities  or other symptoms of congenital ZIKV infection in whom the mother had potential exposure to the virus, should be tested. This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology. Management is evolving and infants with suspected or confirmed CZS should also undergo further work-up including: routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation as outlined in current guidelines by the Canadian Paediatric Society (CPS)Footnote 77. Care should be taken to ensure a thorough work up for other important and treatable causes of congenital infections, such as cytomegalovirus and toxoplasma. Infants with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae.

Infants born to women with symptoms of active ZIKV infection around the time of delivery are at risk for perinatal transmission of the disease. In the limited number of reported cases to date, perinatally infected infants have exhibited either no or mild symptoms and laboratory findings (rash, thrombocytopenia)Footnote 41. Regardless, such infants should be monitored closely given the unclear spectrum of potential illness in this emerging infection. Testing with serology and serum PCR during acute illness is recommended.

Treatment

Currently there is no specific therapy for the treatment of ZIKV infection. Treatment is supportive with antipyretics (acetaminophen in pregnancy), hydration and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out to reduce the risk of hemorrhageFootnote 78. Symptomatic disease typically lasts for up to seven days. Urgent medical care is recommended for any symptoms associated with GBS, and treating health care providers should be made aware of recent travel to area with ZIKV circulation and/or symptoms of ZIKV infection.

If ZIKV infection is confirmed in the setting of pregnancy, referral to a Maternal Fetal Medicine Specialist or specialist familiar with Reproductive Infectious Diseases should be made. If microcephaly, intracranial calcifications or other abnormalities are identified, appropriate counselling by a Neonatologist and Pediatric Infectious Diseases Specialist on potential neurodevelopmental outcome should be offered to parents.

Recommendations for ZIKV

Recommendations
Action Group Recommendation

Decision to travel to areas of risk

All travellers

Health care providers should discuss current knowledge about ZIKV, associated risks, and preferences and values with patients. Some travellers may wish to postpone travel to areas of risk.

Pregnant women

 Pregnant women should avoid travel to areas of risk.

Women planning a pregnancy

Women planning a pregnancy should consider postponing travel to areas of risk.

Prevention of mosquito borne transmission

All travellers

All travellers to areas of risk should strictly adhere to recommendations for the use of personal protective measures against mosquito bites through all hours of the day and night.

Prevention of sexual transmission

Pregnant women and their partner

Couples should practise abstinence or use condoms while in a risk area.

Pregnant women or female partners who have been in a risk area should follow the same precautions as are recommended for non-pregnant females after return from a risk area, i.e. use condoms or abstain for 2 months to avoid infecting their partner.

Males who have been in an area of risk should use condoms or abstain for the duration of the pregnancy.

Couples planning a pregnancy

Women planning a pregnancy should wait at least two months after their return from an area of risk before trying to conceive.

Male partners who have travelled in an area of risk should delay trying to conceive for six months after their return.

Couples outside the context of current or planned pregnancy

Male partners who have travelled in an area of risk should consider using condoms for six months after their return.

Female partners who have travelled in an area of risk should consider using condoms or other barrier methods for 2 months after their return.

Screening and Management

All travellers

Testing should be considered for any ill traveller with compatible epidemiologic and clinical history, when symptom onset is within three days after arrival in, to 14 days after departing from an area of risk.

Serology and RNA testing in Canada is only available for symptomatic individuals and pregnant women. Testing of asymptomatic individuals (men or non-pregnant women) is not routinely offered.

Acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity.

Convalescent patient with symptom onset over 10 days ago, only serology should be requested.

Male partners

Serologic testing may be considered for male returned travellers whose clinically compatible illness has resolved, and are at least two weeks post exposure, in order to assess for potential contagiousness to sexual partners.

Serological testing of male individuals with a history of travel to an area with Zika virus transmission but no history of related symptoms will be considered if their partners plan on becoming pregnant within 6 months of travel to an affected area.

Samples should be collected at least two weeks after return and follow up serology several weeks later is advised due to possible variations in immune response to viral infection.

Negative serology

A negative result for a symptomatic or asymptomatic patient (male or female), whether from an initial or follow-up serology (e.g., if the first test is equivocal), indicates that a recent ZIKV infection is very unlikely. In this situation, and outside the context of a current pregnancy, patients (and their partners) might consider forgoing recommendations related to preventing sexual transmission of ZIKV. This decision should be made in consultation with a health care provider, and should be set against the broader context of the likelihood of infection and patient values and preferences.

All pregnant women

All pregnant patients with a travel history to an area of risk should receive a medical evaluation.

Asymptomatic pregnant women

Asymptomatic pregnant women should consider testing; this would consist of serology at least two weeks after the last potential exposure and fetal ultrasounds, (unless found to be seronegative) at a frequency to be determined in consultation with the woman’s obstetrician.

Symptomatic pregnant women

Acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity.

Convalescent patient with symptom onset over 10 days ago, only serology should be requested.
Repeated ultrasound monitoring is indicated, unless the woman found to be negative on laboratory testing, including negative serology at least 2 weeks after the last possible exposure.

Fetus of pregnant women with confirmed or suspected ZIKV infection

Pregnant women with confirmed or suspected ZIKV infection in pregnancy should receive serial ultrasounds (every 3-4 weeks).

Infant born to a woman with confirmed or suspected ZIKV infection or with suspected CZS

Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with microcephaly, intracranial calcifications or other symptoms of CZS in whom the mother had potential exposure to the virus, should be tested.

This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology.

Infants with suspected or confirmed congenital ZIKV infection/ syndrome

Infants with suspected or confirmed congenital ZIKV infection/syndrome should also undergo further work-up including routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation.

Those with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae.
Consult CPS guidelines.Footnote 77

Treatment

Pregnant cases

Acetaminophen, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes. Referral to a maternal fetal medicine specialist or infectious diseases specialist should be made. If fetal abnormalities are identified, appropriate counselling should be offered.

Non-pregnant cases

Antipyretics, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes.

Additional resources and useful links

Acknowledgements

This statement was developed by the Zika Working Group: Libman, M (chair), Boggild A, Bui Y, Brophy J, Drebot M, Geduld J, McCarthy A, Safronetz D, Schofield S, Demarsh A, Vanschalkwyk J, Yudin M and approved by CATMAT.

CATMAT acknowledges and appreciates the contribution of Elspeth Payne to this statement.

CATMAT members: McCarthy A (Chair), Acharya A, Boggild A, Brophy J, Bui Y, Crockett M, Greenaway C, Libman M, Teitelbaum P and Vaughan S.

Liaison members: Audcent T (Canadian Paediatric Society) and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).

Ex officio members: Marion D (Canadian Forces Health Services Centre, Department of National Defence), Rossi C (Medical Intelligence, Department of National Defence), McDonald P (Bureau of Medical Sciences, Health Canada) and Schofield S (Pest Management Entomology, Department of National Defence).

Conflict of interest

None declared.

References

Footnotes

Footnote 1

World Health Organization. Zika virus situation reports. 2016; Available at: http://www.who.int/emergencies/zika-virus/situation-report/en/. Accessed October 4, 2016.

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Footnote 2

Centers for Disease Control and Prevention (CDC). Advice for people living in or traveling to South Florida. 2016; Available at: http://www.cdc.gov/zika/intheus/florida-update.html. Accessed October 4, 2016.

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Footnote 3

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Footnote 4

Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009;15(9):1347-1350.

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Kraemer MU, Sinka ME, Duda KA, Mylne AQ, Shearer FM, Barker CM, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife 2015;4(e08347):1-18.

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Triunfol M. A new mosquito-borne threat to pregnant women in Brazil. Lancet Infect Dis 2016;16(2):156-157.

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Footnote 7

World Health Organization. Surveillance for Zika virus infection, microcephaly and Guillain-Barré syndrome Interim guidance 7 April 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204897/1/WHO_ZIKV_SUR_16.2_eng.pdf?ua=1. Accessed April 12, 2016.

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Footnote 8

Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, et al. Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet 2016;ePub.

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Schuler-Faccini L. Possible Association Between Zika Virus Infection and Microcephaly—Brazil, 2015. Morb Mortal Wkly Rep 2016;65(3):59-62.

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Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika Virus Associated with Microcephaly. N Engl J Med 2016;374:951-958.

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Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects — Reviewing the Evidence for Causality. N Engl J Med 2016;ePub.

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Footnote 12

de Araujo TV, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo AP, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. Lancet Infect Dis 2016 Sep 15.

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Russell K, Oliver SE, Lewis L, Barfield WD, Cragan J, Meaney-Delman D, et al. Update: Interim Guidance for the Evaluation and Management of Infants with Possible Congenital Zika Virus Infection - United States, August 2016. MMWR Morb Mortal Wkly Rep 2016 Aug 26;65(33):870-878.

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Franca GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 2016 Aug 27;388(10047):891-897.

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European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome, 10 December 2015. 2015; Available at: http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdf. Accessed Feb. 2, 2016.

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Brito Ferreira ML. Neurologic Manifestations of Arboviruses in the Epidemic in Pernambuco, Brazil. American Academy of Neurology 68th Annual Meeting 2016.

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Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015;21(2):359-361.

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Footnote 19

Foy BD, Kobylinski KC, Chilson Foy JL, Blitvich BJ, Travassos da Rosa A, Haddow AD, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011;17(5):880-882.

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Footnote 20

Dallas County Health and Human Services. DCHHS Reports First Zika Virus Case in Dallas County Acquired Through Sexual Transmission. 2016; Available at: http://www.dallascounty.org/department/hhs/press/documents/PR2-2-16DCHHSReportsFirstCaseofZikaVirusThroughSexualTransmission.pdf. Accessed Feb. 2, 2016.

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Footnote 21

Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, et al. Transmission of Zika Virus Through Sexual Contact with Travelers to Areas of Ongoing Transmission — Continental United States, 2016. Morb Mortal Wkly Rep 2016;65(8):215-216.

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Footnote 22

Deckard DT, Chung WM, Brooks JT, Smith JC, Woldai S, Hennessey M, et al. Male-to-Male Sexual Transmission of Zika Virus — Texas, January 2016. Morb Mortal Wkly Rep 2016;65(14):372-374.

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Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. New Engl J Med 2009;360(24):2536-2543.

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Cao-Lormeau VM, Roche C, Teissier A, Robin E, Berry AL, Mallet HP, et al. Zika virus, French Polynesia, South Pacific, 2013. Emerg Infect Dis 2014;20(6):1085-1086.

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Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol 2015;68:53-55.

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Footnote 30

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Tognarelli J, Ulloa S, Villagra E, Lagos J, Aguayo C, Fasce R, et al. A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch Virol 2015;ePub.

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Footnote 33

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Footnote 34

Bogoch II, Brady OJ, Kraemer MU, German M, Creatore MI, Kulkarni MA, et al. Anticipating the international spread of Zika virus from Brazil. Lancet 2016;387(10016):335-336.

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Footnote 37

Lessler JT, Ott CT, Carcelen AC, Konikoff JM, Williamson J, Bi Q, Kucirka LM, Cummings DA, Reichd NG,Chaissona LH. Times to key events in the course of Zika infection and their implications: a systematic review and pooled analysis. Bull World Health Organ 2016.

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Footnote 38

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Mansuy JM, Suberbielle E, Chapuy-Regaud S, Mengelle C, Bujan L, Marchou B, et al. Zika virus in semen and spermatozoa. Lancet Infect Dis 2016 Oct;16(10):1106-1107.

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Footnote 40

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Footnote 41

Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal transmission of zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014;19(13):20751.

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Footnote 42

Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo De Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: Tip of the iceberg? Ultrasound Obstet Gynecol 2016;47(1):6-7.

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Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveil 2014;19(14):20761.

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Freour T, Mirallie S, Hubert B, Splingart C, Barriere P, Maquart M, et al. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro Surveill 2016 Jun 9;21(23):10.2807/1560-7917.ES.2016.21.23.30254.

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World Health Organization. Zika virus, Microcephaly and Guillain-Barré Syndrome Situation Report 26 February 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204491/1/zikasitrep_26Feb2016_eng.pdf?ua=1. Accessed March 4, 2016.

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Footnote 59

Cao-Lormeau V, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016;ePub.

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Mécharles S, Herrmann C, Poullain P, Tran T, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet 2016;ePub.

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Carteaux G, Maquart M, Bedet A, Contou D, Brugières P, Fourati S, et al. Zika Virus Associated with Meningoencephalitis. N Engl J Med 2016;ePub.

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Karimi O, Goorhuis A, Schinkel J, Codrington J, Vreden SGS, Vermaat JS, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet 2016;387:939-940.

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Baud D, Van Mieghem T, Musso D, Truttmann AC, Panchaud A, Vouga M. Clinical management of pregnant women exposed to Zika virus. Lancet Infect Dis ;16(5):523.

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Sarno M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, et al. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLOS Negl Trop Dis 2016;10(2):e0004517.

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Melo AS, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, et al. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurol 2016 Oct 3.

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Brasil P, Pereira J,Jose P., Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report. N Engl J Med 2016;ePub.

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Footnote 72

Government of Canada, Government of Canada. Zika virus. 2016; Available at: http://www.healthycanadians.gc.ca/diseases-conditions-maladies-affections/disease-maladie/zika-virus/index-eng.php?utm_source=zika_virus_16&utm_medium=banner_en&utm_campaign=phacfeaturebox. Accessed October 4, 2016.

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Footnote 76

Calvet G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016;ePub.

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Footnote 77

Canadian Paediatric Society (CPS). Zika Virus: What does a physician caring for children in Canada need to know? 2016; Available at: http://www.cps.ca/en/documents/position/Zika-virus. Accessed December 20, 2016.

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Footnote 78

Centers for Disease Control and Prevention (CDC). Clinical Evaluation & Disease. 2016; Available at: http://www.cdc.gov/zika/hc-providers/clinicalevaluation.html. Accessed Feb. 5, 2016.

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