By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: While the Zika virus has been indolent in many South American, Central American, and Caribbean countries, its recent association with microcephaly (and neurologic impairment) has created an outburst of media alerts, response from the Centers for Disease Control and Prevention, and travel recommendations, particularly as the world moves closer to the 2016 Summer Olympics in Brazil.

Zika is a flavivirus that was first described as causing infection in humans in the Zika Valley in Uganda. It is carried by the mosquito, Aedes aegypti, which also carries dengue fever, yellow fever, and chikungunya viruses. Although this virus-transporting mosquito is common in the United States, especially in the South, the few cases diagnosed in North America have been in those individuals returning from countries in South America and the Caribbean, where outbreaks are currently occurring.

Zika-related infection is mostly silent, but in about 20% of cases it can be associated with fever, headache, myalgias, a maculopapular rash, and conjunctivitis.1 The viremia rarely lasts more than 1 week. However, on a few occasions it has been associated with Guillain-Barré syndrome in adults, resulting in neuromuscular weakness and, occasionally, temporary paralysis. What has elicited the most concern is its association with microcephaly in fetuses and newborns in mothers infected with the virus. The Zika virus has been isolated from maternal blood, amniotic fluid, placenta, and brain tissue. Interestingly enough, it has also been isolated from semen in adult males. What this means for the fertile couple considering pregnancy has yet to be determined. Thus far, there is no evidence that the virus is transferred through saliva.

A 2014 case in French Polynesia raised the possible association of Zika with microcephaly.2 During the past year, there was a rapid rise of microcephaly in newborns in Brazil, with the provinces of Pernambuco and Bahia particularly hard-hit. According to the Brazil Ministry of Health, less than 150 cases were reported in Brazil in 2014, but this figure rose to more than 4000 cases of microcephaly in 2015 (up until October 2015).3 Of the 732 cases of microcephaly investigated, 270 were truly microcephalic and only possibly linked to Zika. Inconsistent definitions used for microcephaly (2 or 3 standard deviations [SD] below the mean, or head circumferences of 32 cm at term) have hampered attempts to accurately diagnose the condition. In addition, the viral infection can be difficult to characterize. For example, in Bahia, 165 cases of microcephaly were identified, and of the first 35 that were thoroughly scrutinized, 27 were discarded.

Nevertheless, it is clear that there has been a substantial increase in microcephaly in areas of greatest Zika exposure, and the virus has been identified in some mothers of microcephalic infants and, in a few cases, in fetal tissue recovered from demised infants.

DIAGNOSIS OF ZIKA INFECTION

Reverse transcriptase–polymerase chain reaction (RT-PCR) has been used to identify the virus from human tissue, and the presence of Zika IgM in maternal serum signifies a very recent infection. Since the PCR test may cross-react with other viruses (in particular, dengue), patients who test positive should have confirmatory testing. Examining maternal serum for the presence of neutralizing antibodies for dengue and Zika via plaque reduction neutralization testing distinguishes these viruses from one another. If there is a fourfold difference in favor of the Zika, the test is presumed positive. If there is less than a fourfold difference, then the result is inconclusive. More importantly, if the IgM is negative for Zika, then infection is unlikely. The problem with the Zika RT-PCR is that after 5 to 7 days, the virus may not be present in maternal serum (while still being present in amniotic fluid), so a negative test should be backed up with antibody testing for IgM. Maternal serum specimens can be channeled through State Health Departments or the Centers for Disease Control and Prevention (CDC; 800-232-4636).

DIAGNOSIS OF MICROCEPHALY

Discrepancy in the definition of microcephaly is the main reason experts in Brazil have struggled with presenting an accurate incidence of microcephaly. The discrepancy between expected cases of microcephaly and actual cases reported occurred because the head circumference charts applied were not uniform and the thresholds used to define microcephaly were different (as noted above). Also, since most infants/fetuses with small heads are simply genetically predisposed to being small, some investigators will label microcephaly according to whether there is documented pathology. For example, in Brazil, where there have been about 3 million births per year, there were only 143 cases of microcephaly reported in 2014. Even using a head circumference threshold of > 3 SD below the mean, this would suggest a major underreporting of the condition in 2014.

Only very recently has information been available regarding how the Zika virus attacks the brain. In one recent report involving two documented cases of Zika-related microcephaly, the virus seemed to be an equal opportunity attacker of most parts of the fetal brain.4 On prenatal ultrasound, a combination of findings were noted: ventriculomegaly, periventricular calcifications, agenesis of the corpus callosum, small thalami, hypoplasia of the cerebellar vermis, large cisterna magna, as well as large subarachnoid space (interestingly, many of these also accompany perinatal cytomegalovirus infection). Although the early cases from Brazil suggested the damage is related to first trimester exposure, more recent cases have been in second and third trimester infections, with particular predilection for the frontal potions of the brain in late infections. In vitro investigation5 has pointed to a direct effect on cortical progenitor cells resulting in cell attenuation, which would explain how the brain shrinks to create the microcephalic infant. Each of the findings noted above potentially is diagnosable with ultrasound and could translate into severe neurological disabilities, as well as hearing loss and blindness.

PREVENTION

Presently, there is no anti-Zika vaccine nor is there an antiviral treatment that will combat this infection. Every effort should be made to avoid or kill the mosquito vector to limit potential exposure to the virus. In Florida, there have been a few cases of perinatal Zika infection, all from travel-related activity. This has triggered increased education and measures to prevent the vector from causing harm. For instance, mosquito spraying and resident alerts (to eliminate or report any locations with even small amounts of standing water, where mosquitoes love to breed) are two such measures. Precautionary measures are particularly stringent for fertile women. Currently women who are pregnant or trying to conceive should avoid traveling to target countries (see the CDC website list at http://wwwnc.cdc.gov/travel/page/zika-travel-information). Partners returning from these countries should either avoid intercourse completely or use condoms for the rest of the pregnancy. CDC recommends that pregnant women with or without symptoms should be offered serum testing with RT-PCR (according to the timing of possible exposures) and antibody testing on their return.6 If they show any flu-like symptoms, they should have PCR testing within a week of the symptoms and IgM antibody analysis 2-12 weeks following exposure/symptoms.

If a positive diagnosis of Zika is made, then a trans-abdominal ultrasound in late second trimester or third trimester can diagnose microcephaly using a head circumference of > 2 SDs below the mean. A transvaginal approach can diagnose some of the subtle brain abnormalities if the fetus is in a vertex presentation. Amniocentesis can be considered after 15 weeks, looking for Zika RT-PCR, to help with pregnancy decision-making.

An optimistic note: Although the Zika outbreak is a real threat to women and their children, the threat could run its course with time in some problem areas, as evidenced by a rapid drop in the number of infected cases in French Polynesia.

REFERENCES

  1. Duffy MR, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009;360:2536-2543.
  2. Besnard M, et al. Evidence of perinatal transmission of the Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014;19:pii:20751.
  3. Schuler-Faccini L, et al. Possible association between Zika virus infection and microcephaly – Brazil, 2015, MMWR Morb Mortal Weekly Rep 2016;65:59-62.
  4. Oliveira Melo AS, et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: Tip of the Iceberg? Ultrasound Obstet Gynecol 2016;47:6-7.
  5. Tang H, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016;18:1-4.
  6. Petersen EE, et al. Interim guidelines for pregnant women during a Zika virus outbreak – United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65:30-33. Doi: 10.15585/mmwr.mm6502e1.