In May 2015, the World Health Organization confirmed the first local mosquito-to-human transmission of Zika virus in the Americas in Brazil. The virus spread rapidly through the country; by the end of 2015, the Brazilian Ministry of Health estimated that between 440,000 and 1,300,000 cases of Zika virus disease had occurred.1 In October 2015, officials noted an unusual increase in the number of newborns with microcephaly in the state of Pernambuco in northeast Brazil, and by the end of 2015 more than 3,500 newborns with microcephaly were reported nationally.2 It is not known how many of these cases are associated with Zika virus infection. Limited evidence, including epidemiologic and laboratory data, support an association between Zika virus infection during pregnancy and congenital microcephaly. Initial epidemiologic investigations found an association between microcephaly and a maternal rash-like illness suggestive of a possible Zika virus infection.2,3 In addition, amniotic fluid obtained from two pregnancies affected by microcephaly was positive for Zika virus RNA,4 and laboratory testing demonstrated Zika virus infection in tissue from three neonates with microcephaly and from two fetal losses.1 Based on this information, the Centers for Disease Control and Prevention (CDC) issued travel advisories on January 15, 2016, for pregnant women to consider postponing travel to areas with ongoing Zika virus transmission.1 For women of reproductive age residing in areas with ongoing transmission of Zika virus, CDC recommends that health care providers discuss pregnancy intention and reproductive options.5
As of January 29, 2016, local transmission of Zika virus had been identified in at least 22 countries or territories in the Americas, including the Commonwealth of Puerto Rico and the U.S. Virgin Islands (Fig. 1). Given the current spread of the virus, obstetric health care providers need to know about Zika virus and its potential effects during pregnancy. We review information on Zika virus, its clinical presentation, modes of transmission, laboratory testing, effects during pregnancy, and methods of prevention to assist health care providers caring for pregnant women during a Zika virus outbreak.
ZIKA VIRUS INFECTION
Zika virus is a mosquito-borne flavivirus that was first identified in Uganda in a monkey in 1947.6 It is transmitted by the Aedes (Stegomyia) species of mosquitoes, most commonly Aedes aegypti, which also transmit yellow fever, dengue, and chikungunya viruses. Zika virus also has been identified in Aedes albopictus mosquitoes.7 Both Aedes species of mosquitoes are present in the United States. Aedes aegypti can be found in limited areas of the South, whereas Aedes albopictus has a wider distribution across the Southeastern United States and into the Midwest.8 These mosquitoes live in and around households and lay eggs in domestic water-holding containers. Aedes (Stegomyia) species of mosquitoes are daytime biters.9 Individual cases of Zika virus disease in humans were first reported in Africa and southeast Asia. The first outbreak of Zika virus disease occurred on the Pacific island of Yap in 2007. Forty-nine confirmed cases and 59 probable cases of Zika virus disease were identified10; however, approximately 73% of the population of 7,391 persons was estimated to be infected during the outbreak. In 2013–2014, more than 28,000 cases of suspected Zika virus disease were reported in French Polynesia and other Pacific islands.11 Genetic analysis suggests that the Zika virus currently circulating in Brazil originated from viral strains circulating in French Polynesia and nearby islands.12
About one in five people infected with Zika virus become ill.6 The incubation period for Zika virus is unknown, but preliminary data suggest an incubation period similar to that of other flaviviruses, likely a few days to 2 weeks. The most common manifestations are acute onset of fever, maculopapular rash, arthralgia, and conjunctivitis; myalgia, headache, retro-orbital pain, pruritus, and vomiting also have been reported. Symptoms are generally mild and last for several days to 1 week; severe illness is uncommon, and deaths associated with Zika virus infection are rare.10 Guillain-Barré syndrome has been reported in patients following suspected Zika virus infection.13 Symptoms of Zika virus disease are similar to those of other diseases spread by Aedes aegypti species (ie, chikungunya and dengue) and similar to other infectious diseases including malaria, rubella, measles, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsia, and group A streptococcal infections.
Although the most common mode of transmission of Zika virus to humans is from the bite of an infected mosquito, other modes of transmission have been documented, including maternal–fetal transmission. Transmission through blood transfusion14 and laboratory exposure15 also have been reported. Three cases of probable sexual transmission of Zika virus have been reported.16–18 The length of time that Zika virus remains in semen is unknown.18 Zika virus RNA has been identified in breast milk, but attempts to culture the virus were unsuccessful. Transmission through organ or tissue transplantation is theoretically possible, but has not been documented.1
Zika virus testing can be performed to detect the presence of viral RNA, antigen, or antibodies. Reverse transcription-polymerase chain reaction (RT-PCR) has been validated, and its performance has been evaluated in individuals with symptoms consistent with Zika virus disease.19 Reverse transcription-polymerase chain reaction testing to detect Zika virus RNA can be performed on serum, amniotic fluid, and other fluids, as well as tissues. Reverse transcription-polymerase chain reaction testing of serum is recommended within approximately 1 week of symptom onset. Viral clearance can occur within 7 days of symptom onset; thus, a negative RT-PCR result on a test performed 5–7 days after symptom onset may not exclude Zika virus infection.20–22 Immunohistochemical staining also can be used to detect Zika virus antigen in tissues, including within placental tissues.23,24 Serologic testing can detect immunoglobulin M (IgM) by enzyme-linked immunosorbent assay as early as 4 days after illness onset19; however, a negative result on serum collected less than 7 days after illness onset does not exclude Zika virus disease. In addition, a positive IgM result can be difficult to interpret; cross-reaction due to previous flavivirus exposure, including vaccination (eg, yellow fever vaccine) and infections (eg, dengue virus), can occur. Zika virus IgM levels may be elevated as a result of this cross-reaction. Plaque-reduction neutralization testing can be performed to measure virus-specific neutralizing antibodies to Zika virus and other flaviviruses. The levels of neutralizing antibodies can be compared between flaviviruses, but these tests may be difficult to interpret in individuals previously infected or vaccinated against flaviviruses. Health care providers are encouraged to work with their health departments to facilitate interpretation of Zika virus tests.
As of February 12, 2016, commercial tests for Zika virus are not available. Zika virus IgM and plaque-reduction neutralization testing is performed only at CDC and a limited number of state and local health departments. Health care providers should contact their state or territorial health department for assistance with arranging testing and interpreting results. As an arboviral disease, Zika virus disease is a nationally notifiable condition and laboratory-confirmed cases should be reported to the state, territorial, or local health department.
ZIKA VIRUS INFECTION DURING PREGNANCY AND EFFECTS ON THE FETUS
Data on pregnant women infected with Zika virus are limited. Pregnant women can be infected with Zika virus in any trimester, and symptoms reported during pregnancy are similar to those in nonpregnant individuals. No evidence exists to suggest that pregnant women are more susceptible to Zika virus infection or are more severely affected once infected.4,25
Maternal–fetal transmission of Zika virus has been demonstrated throughout pregnancy.4,25 The full spectrum of outcomes that might be associated with congenital Zika virus infection is unknown; however, microcephaly, brain atrophy, ventricular enlargement, and intracranial calcifications have been reported in neonates who have tested positive for Zika virus infection.4 Ocular defects, scalp rugae, and joint contractures also have been reported in cases of suspected congenital Zika virus infection (ie, neonates with microcephaly for whom Zika virus testing had not been performed).3,4,25,26 In addition to the association with brain abnormalities in neonates, Zika virus RNA has been detected in the pathologic tissue specimens of fetal losses; however, it is unknown whether Zika virus caused the fetal loss.27 An analysis of data from French Polynesia, performed retrospectively after identification of an increase in cases of microcephaly in Brazil, demonstrated an increase in the number of central nervous system anomalies in fetuses and neonates during 2014–2015. Anomalies include microcephaly, destruction of cerebral structure, cerebellar agenesis, and ventricular dilation. Although results of Zika virus testing are not available, based on the epidemiology of Zika, the timing of these cases would correspond to possible exposure to Zika virus during the first and second trimesters of pregnancy.28 The frequency of maternal–fetal transmission and the risk that a fetus infected with Zika virus will develop microcephaly or other congenital defects are unknown. It is also unknown whether the timing or severity of symptoms, viral load, maternal immune response, or other factors increase the risk of mother–fetal transmission or of the occurrence of abnormalities.
In a registry of 35 children with microcephaly in Brazil, all mothers had lived in or visited areas of active Zika transmission during pregnancy, and 72% reported a rash illness during pregnancy. However, none of the 35 children or their mothers had been tested for Zika virus (results on the children were pending at the time of publication of this case series). Among these 35 children, 74% (n=28) had severe microcephaly, almost half had at least one neurologic abnormality, and all who had undergone neuroimaging (n=27) had evidence of structural brain abnormalities.3 In addition, almost one fifth of the children had ocular abnormalities, consistent with a previous report of suspected prenatal Zika virus infection in which three children with microcephaly had macular lesions.26
In addition to transmission during pregnancy, peripartum transmission of Zika virus has been reported in two mother–newborn pairs during the 2013–2014 French Polynesian outbreak.25 In one case, the mother developed a mild pruritic rash 2 days before delivery. Zika virus RNA was detected in maternal serum 2 days after delivery, and serum obtained from the newborn on the third day of life was positive for Zika virus RNA. Based on symptoms and subsequent testing, the mother was likely viremic at the time of the delivery, suggesting peripartum transmission. In the second mother–newborn pair, Zika virus RNA was detected in maternal serum 1 day after delivery, with the subsequent development of mild fever and rash. Zika virus RNA was detected in the newborn on the first day of life, coincident with the development of a maculopapular rash. This newborn also developed thrombocytopenia and was of low birth weight.25
Microcephaly is a condition in which a neonate's head is smaller than expected compared with neonates of similar gestational age and sex. Congenital microcephaly can be detected prenatally, but most commonly is detected after birth. No definition of microcephaly has been universally accepted; definitions have included a head circumference 3 or more or 2 or more standard deviations below the mean or less than the 3rd or 5th percentiles. Because of varying definitions, the birth prevalence of congenital microcephaly is difficult to monitor in a population. In the United States, estimates of the birth prevalence range from 2 to 12 affected newborns per 10,000 live births.29 No population-based estimates of the birth prevalence of congenital microcephaly were available in Brazil before the observed increase in Zika virus infection. However, the number of newborns with severe microcephaly currently being reported in Brazil appears to be much greater than expected based on hospital-based data from previous years.2
Although neonatal head circumference may correlate with the volume of the underlying brain,29 it can be difficult to predict long-term consequences based on head size alone. Children born with severe microcephaly can have seizures, vision or hearing problems, and developmental disabilities including cognitive impairment or cerebral palsy. Manifestations can vary depending on the severity of the microcephaly and underlying insult to the brain.
Several other infections during pregnancy have been associated with microcephaly, including rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, and Toxoplasma gondii (toxoplasmosis).30 Manifestations of these congenital infections include brain abnormalities (eg, intracranial calcifications and hydrocephalus), eye abnormalities (eg, cataracts, glaucoma, and chorioretinitis), and hearing impairment.30 Maternal–fetal transmission of other flaviviruses (ie, dengue, Japanese encephalitis, West Nile virus, and yellow fever viruses) has been reported rarely; available data suggest that these viruses are not associated with an increased risk for congenital defects.31–34 A single case of West Nile virus infection transmitted from mother to fetus during pregnancy showed chorioretinitis and severe cerebral abnormalities consistent with focal cerebral destruction,35 which raised concern for teratogenicity. However, whether West Nile virus infection caused the abnormalities seen in this child is unknown; subsequent studies have not suggested an increased risk.32 In addition to infectious causes, congenital microcephaly can be associated with prenatal exposure to noninfectious agents (eg, alcohol, mercury) and with many genetic conditions.36
Microcephaly may be detected by ultrasonography as early as 18–20 weeks of gestation; however, detection of microcephaly by prenatal ultrasound examination can be challenging.37 The optimal time, sensitivity, specificity, and predictive value of prenatal ultrasound examination for detection of microcephaly are unknown. As with other abnormalities, the detection rates vary based on many factors. These include the type and severity of microcephaly, patient factors (eg, obesity), gestational age and fetal position, equipment used, and the expertise of the ultrasonographer.38 There is no standard definition for fetal microcephaly; it may be suspected if the head circumference is more than 2 or 3 standard deviations below the mean for gestational age. In a recent study of microcephaly from causes other than Zika virus infection, prenatal ultrasound diagnosis of microcephaly at gestational ages ranging from 22 weeks to 38 weeks had a positive predictive value for neonatal microcephaly of about 57%.39
Other abnormalities that have been detected ultrasonographically in association with congenital Zika virus infections include corpus callosal and vermian dysgenesis, enlarged cisterna magna, severe unilateral ventriculomegaly, agenesis of the thalami, cataracts, and intraocular calcifications.4 Therefore, a prenatal ultrasound examination also should include careful assessment of fetal neuroanatomy. The role of fetal magnetic resonance imaging (MRI) for the detection of microcephaly is unknown. Fetal MRI should not be considered a screening tool40; the sensitivity, specificity, and predictive value of MRI for the detection of microcephaly are unknown. Fetal MRI has limited availability in the United States, and interpretation of fetal MRI requires specialized expertise.
RECOMMENDATIONS FOR PREVENTION OF ZIKA VIRUS INFECTION
To assist health care providers who care for pregnant travelers to and residents of areas of Zika virus transmission, CDC has developed interim clinical guidance.5,27 Because there is neither a vaccine nor medications available to prevent Zika virus transmission, CDC recommends all pregnant women consider postponing travel to areas of ongoing Zika virus transmission if possible (updated information on travel advisories is available here: http://wwwnc.cdc.gov/travel/notices). Pregnant women who travel to areas with Zika virus transmission should strictly follow steps to avoid mosquito bites, particularly during the daytime. Mosquito bite–prevention strategies include wearing long-sleeved shirts and long pants, using U.S. Environmental Protection Agency–registered insect repellents, wearing permethrin-treated clothing and gear, and staying and sleeping in screened-in or air-conditioned rooms. When used as directed on the product label, insect repellents containing active ingredients such as DEET, picaridin, and IR3535 are considered to be safe for pregnant and nursing women.1
Data regarding DEET use during pregnancy are reassuring.2 First-trimester DEET exposure of pregnant rats and rabbits did not result in increased rates of malformations in offspring, although low birth weight was observed in offspring with exposure to very high doses.41 A double-blind randomized therapeutic trial involving 897 pregnant women in the second or third trimesters who regularly applied therapeutic doses of DEET topically (20% DEET, similar to that recommended to prevent malaria) did not demonstrate adverse dermatologic, neurologic, or gastrointestinal effects when compared with the control group. No adverse effects were noted on fetal or infant survival, growth, or development up to 1 year of age.41 DEET was detected in only four (8%) cord blood samples from a randomly selected subgroup of 50 DEET users, indicating that the risk of DEET accumulation in the fetus is low. No human data regarding first-trimester exposure to DEET are available; however, based on the animal data and the potential risks of mosquito-transmitted infections, DEET is recommended for use among pregnant women throughout pregnancy. No evidence exists to suggest that reproductive or developmental effects occur in a child after exposure to permethrin.42
Although mosquito-to-human transmission appears to be the main cause of Zika virus infection, sexual transmission is possible. Given the potential risks of maternal Zika virus infection, pregnant women whose male partners reside in or have traveled to an area of ongoing Zika virus transmission should abstain from sexual activity or should use condoms correctly and consistently during sexual activity for the duration of the pregnancy.18
EVALUATION OF PREGNANT WOMEN RESIDING IN OR WITH A HISTORY OF TRAVEL TO AREAS OF ONGOING ZIKA VIRUS TRANSMISSION
Health care providers should ask all pregnant women about recent travel and be aware of areas with ongoing Zika virus transmission. Women who have traveled during pregnancy to an area with ongoing Zika virus transmission and those residing in such areas should be evaluated for Zika virus infection in accordance with CDC guidelines (http://www.cdc.gov/mmwr/volumes/65/wr/mm6502e1.htm).5,27 It is unknown whether asymptomatic maternal infection can lead to fetal infection. Maternal Zika virus testing would depend on timing of symptoms relative to clinical presentation. Because of similar geographic distribution and symptoms, patients with suspected Zika virus infections also should be evaluated and managed for possible dengue or chikungunya virus infection.
Amniotic fluid can be tested for the presence of viral RNA by RT-PCR; however, the sensitivity and specificity of amniotic fluid testing is unknown. In pregnancies that result in fetal loss, Zika virus RT-PCR and immunohistochemical staining can be used to test the fetal and placental tissues. Testing of fetal brain tissue has identified Zika virus.3,24
No specific antiviral treatment is available for Zika virus disease. Treatment is generally supportive and includes rest, fluids, and use of analgesics and antipyretics. Fever during pregnancy has been shown to increase the risk for adverse pregnancy outcomes, including neural tube defects, and should be treated with acetaminophen.43 Aspirin and other nonsteroidal anti-inflammatory drugs generally are not recommended during pregnancy and should be avoided in patients with possible Zika virus disease. If nonsteroidal anti-inflammatory drug use is considered, dengue should be ruled out before use to reduce the risk of hemorrhage.44
Pregnant women with laboratory-confirmed Zika virus infection can be offered amniocentesis to test for Zika virus RNA by RT-PCR after 15 weeks of gestation. Amniocentesis is associated with a less than 0.1% risk of fetal loss when performed after 15 weeks of gestation.45 In cases of maternal Zika virus disease, serial ultrasound examinations should be considered to monitor fetal anatomy and growth every 3–4 weeks. Referral to a maternal–fetal medicine specialist or other appropriate specialists is recommended. When congenital Zika virus infection is diagnosed, delivery should occur in a facility equipped to provide appropriate care.
Since first appearing in the Americas in May 2015, Zika virus has spread rapidly throughout the region and is likely to continue to spread. Obstetric health care providers need to be prepared to counsel pregnant women considering travel to areas with ongoing Zika virus transmission. Providers need to know the signs and symptoms, laboratory testing available, and clinical guidelines for pregnant women potentially infected with Zika virus. Based on currently available data, maternal–fetal transmission of Zika virus may be associated with an increased risk for congenital microcephaly and other abnormalities of the brain and eye. However, many questions remain, including the frequency of transmission from mother to fetus, the frequency of adverse outcomes in fetal Zika virus infection, and the spectrum of pregnancy and neonatal outcomes associated with maternal Zika virus infection. As more information becomes available regarding Zika virus infection in pregnancy, guidelines will be updated. The latest information on Zika virus and pregnancy will be available at: http://www.cdc.gov/zika/hc-providers/index.html.
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