Zika Virus and Its Effects in Pregnancy

RELEASE DATE:

September 1, 2016

EXPIRATION DATE:

September 30, 2018

FACULTY:

Ruth P. Ebiasah, PharmD, MS

Thucuma K. Sise, PharmD, BCPS

Michelle Wildman, PharmD
National Institutes of Health,
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland

FACULTY DISCLOSURE STATEMENTS:

Drs. Ebiasah, Sise, and Wildman have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-16-082-H01-P; 0430-0000-16-082-H01-T
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists and pharmacy technicians. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or cecustomerservice@jobson.com

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists and pharmacy technicians about the effect of Zika infection during pregnancy, modes of transmission, signs and symptoms of infection, and preventive measures.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Describe the characteristics of Zika virus and its various modes of transmission.*
  2. Recognize the clinical presentation of Zika infections, including signs and symptoms, and discuss the tools used to definitively diagnose a Zika infection.*
  3. Identify the potential complications that could affect the fetus as a result of Zika infection during pregnancy.*
  4. Counsel patients on important information about Zika virus, including preventive measures for avoiding exposure to infection.

*Also applies to pharmacy technicians.


ABSTRACT: Recently, a major outbreak of Zika virus occurred in several countries in South and Central America and the Caribbean. The World Health Organization estimated that more than 3 million cases of Zika infection would occur in the Americas in 2016, spurring the global community to develop preventive and supportive strategies. Recognizing the signs and symptoms of Zika infection, performing diagnostic tests based on current knowledge, successfully implementing preventive measures, and further evaluating the effects of Zika virus in pregnancy are of chief importance in response to the outbreak. The pharmacist's role in patient counseling and education and the pharmacy technician's role in symptom identification are essential for successfully managing the current outbreak and curbing further spread to the most vulnerable populations, including pregnant women.

Zika virus was first identified in 1947 in the Zika Forest, a research station in Entebbe, Uganda (East African Virus Research Institute, now the Uganda Virus Research Institute).1,2 An outbreak in 2007 in the Yap Islands—where an estimated 75% of the population became infected in a 4-month period—initiated the spread of Zika virus in the Pacific region.3 In 2013, a major outbreak erupted in French Polynesia, and by the beginning of 2014, the first autochthonous transmission cases were reported in New Caledonia, followed by the Cook Islands.4 In 2014, imported cases in travelers to the Pacific area were reported in Norway, Germany, Australia, France, Canada, Italy, and Japan.4 In May 2015, the first cases of the Zika epidemic were reported in Brazil, and the outbreak has since spread through South America, Central America, and the Caribbean. In late July 2016, the Florida Department of Health announced what appeared to be the first cases of local, vectorborne Zika transmission in the continental United States. Florida officials determined that Zika virus was being spread by mosquitoes in Wynwood, a 1-square-mile neigh-borhood in northern Miami.5

Concern over the global threat that Zika virus poses and the potential for birth defects and neurologic complications has gripped communities worldwide. In January 2016, the World Health Organization (WHO) estimated that 3 to 4 million cases of Zika infection, including asymptomatic cases, would occur in the Americas in the next 12 months. The WHO advises that the actions outlined in its Zika Strategic Response Framework be undertaken to control Zika virus disease. This document includes recommendations such as defining and prioritizing research, enhancing surveillance of Zika virus and potential complications, strengthening laboratory capacity for detection, and supporting health authorities’ implementation of vector-control strategies aimed at reducing Aedes mosquito populations. Several countries have also increased their efforts in the wake of the outbreak. Colombia, the Dominican Republic, Ecuador, El Salvador, and Jamaica echo the WHO in advising women to postpone pregnancy until more is known about the virus and its rare, but potentially serious, complications.4

The CDC has published a number of fact sheets that address Zika virus prevention, transmission, risks, and pregnancy considerations, among other topics. The CDC has also issued a level 2 travel warning, which includes the recommendation that pregnant women consider postponing travel to any area with ongoing Zika virus transmission.6 Additionally, in response to the recent local transmission in northern Miami, specific guidance was issued for people who live in or traveled to the affected area any time after June 15, 2016. The guidance includes advice for pregnant women and their partners and for couples planning a pregnancy.5,6

Because of global concerns and the significance of understanding Zika virus and its effects in pregnancy, the pharmacist’s role is becoming increasingly important, particularly with respect to prevention and counseling. Additionally, the role of the pharmacy technician is gaining in importance in terms of symptom identification.

Transmission

Zika virus is an arbovirus of the Flavivirus genus of the Flaviviridae family, which includes dengue, yellow fever, West Nile, Japanese encephalitis, and tickborne encephalitis viruses. Zika virus has been isolated from several species of Aedes mosquitoes, including Aedes africanus, Aedes aegypti, Aedes albopictus, Aedes luteocephalus, Aedes furcifer, and Aedes vittatus; however, only a few species have been implicated in the transmission of Zika virus to humans.7 Although none of the aforementioned arboviruses continuously circulate in the continental U.S., local outbreaks have occurred—and will continue to—as a result of virus importation by infected, viremic travelers (except for West Nile, which is not imported, but endemic in the U.S.). Any viremic traveler visiting or returning to parts of the U.S. with established populations of Ae aegypti or A albopictus mosquitoes could initiate local virus transmission.8

Zika virus is spread in a variety of ways. These modes are commonly defined by the following categories: vector-borne transmission, blood-borne transmission, sexual transmission, and maternal transmission.2

Vector-Borne Transmission: As noted, Zika virus can be transmitted by mosquitoes. Ae aegypti is considered the main vector; however, Ae albopictus also plays a primary role in transmission. Ae albopictus is able to adapt to survive in a broader temperature range and at cooler temperatures than Ae aegypti, and it can be found in the U.S. as far north as New York and Chicago and in parts of southern Europe.9 Both Ae aegypti and Ae albopictus may also transmit dengue and chikungunya.10 Through globalization, both species have been transported throughout the tropics, subtropics, and parts of the temperate world.4,8,10,11 Early laboratory-based studies showed the capacity of Ae aegypti to transmit the virus with an extrinsic incubation period of around 10 days after artificial feeding. Mosquitoes may be infective for up to 60 days after acquiring the virus.11

Blood-Borne Transmission: Transmission of Zika virus via blood transfusion has been suspected in a small number of cases, including two probable cases in Brazil. Zika virus was detected in the blood samples of approximately 3% of blood donors who were asymptomatic during the French Polynesian outbreak. This evidence suggests that there is at least the potential for Zika infection resulting from transmission via infected blood and blood products.12-14 Moreover, in an examination of documented transfusion transmissions of other flaviviruses, such as West Nile, dengue, and yellow fever, all viruses have been proven to cause detectable viremia during asymptomatic and symptomatic infections.15,16 In response to this potential method of Zika transmission, the WHO, CDC, and FDA are carefully monitoring blood-supply safety. The FDA has acted to safeguard the U.S. blood supply, including issuing blood-guidance documents, such as one (in February 2016) outlining recommendations for donor screening, deferral, and product management to reduce the risk of tranfusion transmission of Zika virus (www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM486360.pdf).17,18

Sexual Transmission: Zika infection may be sexually transmitted by males and females who have been infected. Sexual exposure includes vaginal sex, anal sex, oral sex, and other activities that might expose a partner to genital secretions. It is important to note that the transmitting partner does not have to be symptomatic to infect the other person. There have been at least 15 instances of sexual transmission of Zika in the U.S., and additional reports from other countries; however, it has not yet been determined whether Zika virus is more readily transmitted by a female with Zika to a male, or vice versa, or exactly how long the virus remains in bodily fluids.19-23

Because of the lack of serial semen specimens with detectable RNA, the precise duration and pattern of infectious Zika virus in semen remain unknown. However, viral RNA has been detected in semen approximately 60 days after infection. In one case, the virus was isolated from semen at least 2 weeks, and possibly up to 10 weeks, after symptom onset; in another case, it was 6 months after symptom onset.24,25 The longest interval after symptomatic presentation that sexual transmission of Zika virus by a male may have occurred has been reported to be 32 to 41 days.26

Regarding female transmission, there have been reports of Zika virus being transmitted from a symptomatically infected female to a male sex partner.27 Zika virus RNA has been detected in vaginal fluids 3 days after symptom onset and in cervical mucus up to 11 days after symptom onset.28 As a result, sexual partners of infected females may be at risk for infection via exposure to vaginal secretions or menstrual blood.

Sexual transmission to a pregnant woman may have severe implications because the mother may transmit the virus to the developing fetus. It is not clear whether Zika virus that is transmitted sexually to an already-pregnant female has the same risk of birth defects as Zika that is transmitted via a mosquito bite.29

Maternal Transmission: Mother-to-child transmission of Zika virus is not a new phenomenon; it has been reported in the past.30 Current reports related to the most recent outbreak have confirmed this sequela of Zika transmission.4 Vertical transmission can occur during any point of pregnancy through the placental barrier and via perinatal transmission during delivery, resulting in infection of the infant.31 Zika virus has been found in amniotic fluid, placenta, fetal tissues, and paired blood samples from newborn infants and their mothers. Although Zika RNA has been detected in breast milk and the potential exists for viral transmission from a Zika-infected mother to a nursing infant, there have been no reports of virus transmission via breastfeeding.12,32 In utero transmission is the area of greatest concern and urgency because this mode has corresponded with the increase in the number of reported cases of microcephaly.

Signs and Symptoms

About one in five people exposed to Zika virus will develop symptomatic Zika infection. The incubation period (i.e., the time from exposure to symptoms) of Zika virus is unclear, but is likely 2 to 14 days. The symptoms are similar to those in other arbovirus infections, such as dengue and chikungunya.33

Zika infection is characterized by low-grade fever (37.8°C-38.5°C) and, frequently, a maculopapular pruritic rash. Other common symptoms include asthenia, myalgia, arthralgia with possible swelling (notably in the small joints of the hands and feet), and conjunctivitis. Clinical illness is consistent with Zika infection if two or more symptoms are present. These symptoms are usually mild and last for several days to a week after a person is bitten by an infected mosquito.34 However, many people who have been infected with the virus may not realize it because the symptoms often are not severe enough or have a long enough duration to require medical attention.33

Zika virus usually remains in the blood of an infected person for about a week, but it may persist for longer in some people. Once a person has been infected, he or she is likely to be protected from future infections.33

Diagnosis

The presentation of Zika virus is similar to that of dengue and chikungunya.33,34 In one of the earliest documented Zika cases, the patient presented with maculopapular rash, a brief fever, and a mild headache.35,36 Diagnosis was made by taking a sputum collection after resolution of the fever. Patients who present with documented signs and symptoms of Zika infection should be fully evaluated.

The diagnosis of Zika virus requires the clinician to review signs and symptoms, along with laboratory tests. The differential diagnosis must be taken into account, and an extensive travel and residential history should be obtained. Sexual contacts with whom the patient may have had unprotected sex, as well as contacts in general, must be thoroughly reviewed.

A definitive diagnosis of Zika infection is made by laboratory analysis. A polymerase chain reaction (PCR) test taken within the first week of symptom onset can detect viral RNA.33,37,38 Virus-specific immunoglobulin M (IgM) and neutralizing antibodies develop after symptoms have occurred for 1 week. Diagnosis can be difficult, as there is a cross-reaction with other flaviviruses, such as dengue. To distinguish between the different flaviviruses, plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies and to discriminate between cross-reacting antibodies in primary flavivirus infections.39

The type of diagnostic tool used depends on how soon after the onset of symptoms the patient presents. Because reverse transcriptase PCR (RT-PCR) is effective only for a 3- to 7-day window (i.e., while the patient is viremic), RT-PCR urine and serum should be performed when a patient presents on days 1 to 6. A negative RT-PCR does not equate to absence of disease.40 Patients who present between day 7 and day 14 after the onset of symptoms should undergo both urine RT-PCR and Zika virus serologic testing (Zika virus IgM and neutralizing antibody titers). Zika virus serologic testing is an appropriate diagnostic tool for patients who present 15 or more days after symptom onset.

The WHO has developed a system to standardize the reporting of Zika virus cases. There are three classifications: suspected, probable, and confirmed Zika virus (discussed below).35,40

Suspected: Zika virus is suspected when a patient has a rash (maculopapular) and/or fever (37.8°C-38.5°C), along with at least one of the following symptoms (not explained by other medical conditions): arthralgia, arthritis, or conjunctivitis (nonpurulent/hyperemic).

Probable: A case is considered probable when there is IgM antibody against Zika virus (with no evidence of infection with other flaviviruses) and relevant epidemiologic exposure.

Confirmed: A case is confirmed when there is laboratory verification of Zika infection, either by detection of viral RNA or antigen in serum or other samples or by detection of Zika IgM antibody and Zika virus 90% PRNT (PRNT90) titer ≥20 and PRNT90 titer ratio ≥4 compared with other flaviviruses.36,40

Treatment and Prevention

The treatment of Zika virus involves primarily supportive care, such as rest, hydration, antipyretics, and analgesics for symptom management. Nonsteroidal anti-inflammatory drugs and aspirin should not be initiated until dengue has been ruled out because they may increase the risk of hemorrhage in these patients.41 The CDC recommends preventive measures such as protective clothing (long sleeves, long pants, or permethrin-treated clothing) and repellents such as DEET (N,N-diethyl-meta-toluamide) and picaridin, which are safe to use during pregnancy and lactation.19

Prevention consists of barriers to mosquito bites, efforts to control the virus-transmitting mosquitoes, and protected intercourse (for those who may have Zika virus). Patients who are at risk for Zika virus exposure should be advised to use barrier prophylactics, such as condoms, with their sexual partners. The CDC recommends that pregnant women practice abstinence or use condoms correctly and consistently to reduce the risk of sexual transmission.20 Another recommended prevention strategy is to use a dental dam for any oral sexual contact. If a sexual partner has recently traveled to an area with Zika virus, the CDC recommends protected sex or abstinence for at least 8 weeks after the female partner is diagnosed with Zika virus or presents with symptoms, or for 6 months if the partner is male.29

Zika-infected patients rarely require hospitalization. The exception is a patient who presents with Guillain-Barré syndrome (GBS) as a result of contracting Zika virus. GBS, a condition that affects the peripheral nervous system, may be extremely debilitating and is the leading cause of paralysis that is not the result of trauma. A genetic predisposition to GBS may be less of a concern than was once theorized.36,42,43 Although there is no cure or treatment for GBS, supportive care may reduce the effects of GBS. Treatment options for GBS patients include IV immunoglobulin, ICU admission, and possibly respiratory support.36

A vaccine for Zika virus is not available at present; however, early clinical trials of candidate vaccines are ongoing, and the development of a novel mouse model for Zika infections using the current viral strain responsible for outbreaks in Central and South America should facilitate the development of vaccines and other therapies.44-46

Effects in Pregnancy

No evidence currently exists that pregnant women are more susceptible to Zika infection or experience severe disease during pregnancy; however, it is suggested that pregnant women may be viremic longer than nonpregnant women.47 Congenital infections caused by viruses such as Zika can be transmitted to a fetus at any time during pregnancy and can affect multiple organ systems. The greatest risk of abnormalities is associated with Zika infection contracted in the first trimester.19,43 Zika virus has a strong affinity or selectivity for the nervous system and particularly targets cells that are self-renewing or multipotent, but it may attack neuronal cells at all stages of development.48 Some of the complications that may occur during pregnancy and affect the fetus include acquired congenital microcephaly, intracranial calcifications, and ocular abnormalities.49

Microcephaly: After examining clinical evidence, the CDC concluded that Zika virus is a cause of microcephaly and other serious brain abnormalities in infected infants.50 Microcephaly is a neurologic condition in which an infant’s head is smaller than normal compared with those in infants of the same sex or gestational age. The circumference of the head is considered a reliable assessment of the volume of the underlying brain. Microcephaly can be detected by ultrasound at 18 to 20 weeks’ gestation, but it may not be evident until late in the second trimester or early in the third trimester. The causal relationship between Zika virus and microcephaly or other adverse outcomes does not mean that if a woman is infected with Zika virus during pregnancy, the infant will definitely have health problems; it means simply that the infant is at increased risk for microcephaly or other health problems.51

Fetal Intracranial Calcifications: Fetal intracranial calcifications occur when a congenital infection such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, or Zika virus enters the central nervous system of a fetus through the placenta.52 The abnormal deposits of calcium associated with the disorder occur in certain areas of the brain, including the basal ganglia and the cerebral cortex.

Ocular Findings: Zika virus can cause symptoms such as nonpurulent conjunctivitis. Other ocular abnormalities have been observed in infants with microcephaly, according to a case series conducted in December 2015 in Salvador, Brazil. Ocular lesions, the most common of which were macular pigment mottling and chorioretinal scarring, were presumed to be due to exposure to Zika virus in utero.53 Optic-nerve abnormalities, iris coloboma, lens subluxation, active uveitis, and vasculitis were also observed. It is unknown whether these ocular findings are a direct result of Zika infection or are a consequence of microcephaly.53

Other Congenital Effects: Additional congenital signs or symptoms that have occurred in infants whose mothers were infected with Zika virus during pregnancy include craniofacial disproportion, spasticity, seizures, irritability, and brainstem dysfunction, such as feeding difficulties.49

Testing, Evaluation, and Clinical Considerations: Pregnant women who have had possible exposure to Zika virus and do not reside in an area with active transmission should be evaluated for Zika infection. Similarly, pregnant women who reside in an area with active Zika virus transmission should be evaluated and tested in accordance with the CDC interim guidance (FIGURES 1 and 2).54,55





IgM antibody testing should be offered to asymptomatic pregnant women who have traveled to areas with ongoing transmission of Zika virus. Testing should be conducted between 2 and 12 weeks after a pregnant woman returns from travel to areas with ongoing Zika virus transmission. A negative IgM test result 2 to 12 weeks after known exposure suggests that a recent Zika virus infection did not occur, which may obviate the need for serial ultrasounds.

Pharmacist Counseling

Because there is no treatment for Zika infection, pharmacist counseling should focus on prevention, particularly in pregnant women. Patients will have many questions related to travel, signs and symptoms, risk of infection, and preventive measures. It is important for the pharmacist to be aware of the most common questions that may be posed, as well as suitable and relevant responses.19

What should women planning to travel to endemic areas be aware of regarding Zika virus? Pregnant women should avoid unnecessary travel to Zika-endemic areas. For those who cannot avoid such travel, extra precautions should be observed to prevent mosquito bites.1,19 See wwwnc.cdc.gov/travel/page/zika-travel-information.

What are the signs and symptoms of Zika infection? Zika infection can cause a relatively mild illness, as evidenced by fever, headache, joint pain, muscle aches, skin rash, and eye inflammation (pinkeye). The development of GBS, although rare, has also been reported. Immediate attention must be sought if symptoms of GBS occur, such as tingling, weakness, and/or pain in the feet or legs; the inability to control eye or facial movements; incontinence or the inability to control bladder or bowel function. Most people with Zika infection have no symptoms whatsoever.19,33,34

Which pregnant women are at risk for Zika infection? Any pregnant female living in or traveling to regions with vector-borne transmission is at risk. The most up-to-date list of endemic areas is found on the CDC website Travel Health Notices (wwwnc.cdc.gov/travel/notices). Although sexual transmission is probably less common than transmission via direct mosquito bite, pregnant females who engage in sexual intercourse with an infected partner or a partner living in or traveling to endemic areas are also at risk for infection.19

What risks does Zika infection confer on the fetus? Current reports suggest that it is possible for infection to occur in utero. Several neurologic effects of infection have been observed, such as microcephaly, white-matter atrophy, intracranial calcification, and ocular abnormalities.19,53

How can Zika infection be prevented, and is there a treatment? Until a vaccine becomes available, prevention is the primary form of protection. For individuals who cannot avoid travel to endemic areas, extra precautions should be observed to prevent mosquito bites, such as wearing long sleeves and pants, using insect repellent, and using mosquito netting while indoors. There is no antiviral treatment for Zika infection, so management involves rest, hydration, analgesics, and antipyretics.19

Conclusion

Protection and prevention are critical in stemming the spread of Zika virus. Because there are multiple mechanisms by which Zika virus is transmitted, a clear understanding of each mechanism is essential for recommending appropriate interventions. There are many opportunities for the pharmacist to play an integral role in the education and counseling of patients who are pregnant or are planning a pregnancy. The identification of potential signs and symptoms of infection is crucially important for the pharmacy technician to be aware of when working in partnership with the pharmacist. A thorough knowledge of Zika virus, methods of transmission, and preventive measures, as well as potential effects during pregnancy, is critical to successful engagement with the patient. As methods of transmission and the spread of new cases continue to be reported, the involvement of all health-care providers is of paramount importance. Early discussions with patients prior to travel to endemic areas, in the presence of pregnancy or when pregnancy considerations are being made by couples, are particularly helpful and critical in curbing the spread of this infection.

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