Zika virus and microcephaly

Dr Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South Florida, Tampa.

Last February, an epidemic of a rash-associated mild viral illness rapidly spread through a number of northeastern Brazilian states. By May, the illness was confirmed to be due to the mosquito-borne Zika virus.¹ On November 11, 2015, the Brazilian Ministry of Health declared a public emergency precipitated by reports of a 10-fold higher rate of fetal microcephaly occurring in these same Zika-affected states.

On November 17th the Brazilian Ministry of Health reported that reverse transcription polymerase chain reaction (RT-PCR) analysis of amniotic fluid obtained from 2 women with microcephalic fetuses demonstrated the presence of Zika virus RNA. The same day the World Health Organization (WHO) issued an epidemiological alert regarding the increased occurrence of microcephaly in northeast Brazil. A few days later health authorities in French Polynesia reported at least 17 cases of fetal or infant central nervous malformations associated with an earlier outbreak of Zika virus.

More: What you need to know about Zika virus

In December, the Centers for Disease Control and Prevention (CDC) reported a single autochthonous Zika infection in Puerto Rico and on January 15, 2016, the CDC issued a travel advisory to pregnant women recommending they postpone travel to Mexico, Puerto Rico, and parts of Central America and South America due to the presence of the Zika virus.² On January 22 the advisory was expanded to include parts of the Caribbean and Polynesia. In El Salvador, health officials went so far as to recommend that women postpone becoming pregnant until 2018.

What is this new obstetrical infectious threat, how serious is it, and how should ob/gyns respond?

Zika virus

The Zika virus is one of 4 tropical, arthropod-transmitted viruses to threaten the United States in the past 25 years, the others being dengue, West Nile, and chikungunya. The ecological reasons for this pathogenic onslaught are debatable, but climate change, accelerated globalization of trade, and unfavorable mutations may be factors. Zika was first described in Uganda in 1947 and until recently was confined to a very narrow Afro-Asian equatorial band.¹

Over the past decade the virus has spread across Polynesia to Easter Island, and more recently into Chile, Brazil, Columbia, Suriname, and now into Central America, Mexico, and the Caribbean. This RNA flavivirus is transmitted by the Aedes aegypti mosquito with a 3- to 12-day incubation period. Three-quarters of infections are asymptomatic and when symptomatic, the disease has relatively mild manifestations, including low-grade fever, transient arthritis, a maculopapular rash starting on the face and spreading to the body, mild conjunctivitis, myalgia, headache, and asthenia.¹ This presentation is similar to mild dengue and chikungunya viral infections.

Of note, the French Polynesia and Brazilian outbreaks have also been associated with a significant increase in post-viral Guillain-Barre syndrome.^1,3 A case described in 2013 in Tahiti by Musso et al supports the possibility that Zika could be sexually transmitted, but more investigation into this hypothesis is needed.⁴ Zika’s relatively mild, nonspecific, viral presentation coupled with the absence of commercially available serological or molecular RT-PCR testing makes rendering a definitive clinical diagnosis difficult.

NEXT: Examining the virus-microcephaly link

The virus-microcephaly link

Beyond the tight temporal and geographic correlation between the virus’ explosive spread into Northeast Brazil and the subsequent 10- to 20-fold increase in microcephaly diagnoses in that area,^1,3 a very recent publication by Oliveira-Melo and colleagues provides strong clinical support for the Zika virus’ fetal neuropathic effects.⁵ These authors reported 2 pregnant patients with microcephalic fetuses who had Zika virus RNA identified in their amniotic fluid by RT-PCR. The first patient presented at 30.1 weeks with sonographic evidence of fetal microcephaly (head circumference 2.6 significant deviations [SD] below expected value), extensive cerebral white matter calcifications, and dysgenesis of the corpus callosum and cerebellar vermis.

The second patient had an ultrasound at 29.2 weeks that revealed a head circumference 3.1 SD below the expected value as well as severe unilateral ventriculomegaly, mild cerebral calcification, and bilateral cataracts.

Related: SMFM Consult on diagnosing and antenatal management of CMV infection

To be clear, the link between Zika and fetal microcephaly remains epidemiologically and clinically correlative. Microcephaly is generally defined as a head circumference more than 2 to 3 SD below the mean, corrected for age and sex. Etiologies include genetic causes (eg, aneuploidy, microdeletions, and monogenic disorders), teratogens (eg, alcohol), metabolic disorders (eg, phenylketonuria), malnutrition, hypoxic-ischemic encephalopathy, stroke, and various infectious agents. The last potentially include West Nile virus, another Aedes aegypti-borne RNA flavivirus.⁶ Of course, the most common infectious cause of microcephaly is cytomegalovirus, the prevalence of which vastly dwarfs that of Zika in North America and worldwide.⁷

What is the magnitude of the Zika threat?

The thought of a pandemic virus that causes a severe fetal neurodevelopmental abnormality and for which there is no ready clinical diagnostic work-up, preventative vaccine, or antiviral therapy is chilling. However, several points place this latest tropical-derived epidemic in perspective. In the very heart of the Brazilian epidemic-the city of Salvador in Bahia State, which has the ideal climatic conditions (wet, hot, and humid) for this mosquito-transmitted virus-the attack rate is only 5.5 cases/10,000 inhabitants.

By November 28, 2015, 646 microcephaly cases had been described in Brazil’s hard-hit Pernambuco state, which has a population of more than 9 million.⁵ In the French Polynesian outbreak, only 17 cases of various fetal/pediatric neurodevelopmental abnormalities were reported among a potential population of 32,000 infected people.³ Furthermore, while a 10- to 20-fold increase in microcephaly sounds terrifying, the actual prevalence of the anomaly in the United States is lower than 6 per 10,000 live births.⁸

While these statistics are somewhat reassuring, there is also concern that the virus could adapt to be transmitted by the Aedes albopictus mosquito, whose habitat includes 32 states in the United States³; indeed an infected A. albopictus has been identified in Gabon.¹

NEXT: What do ACOG and SMFM have to say?

Take-home message

While researchers ascertain the magnitude of the Zika virus threat to pregnant women, and steps are taken to develop appropriate serological and molecular diagnostic tests, pregnant women should adhere to the CDC travel advisory. For pregnant women who reside in, or must travel to, areas affected by the pandemic, CDC-recommended precautions should be taken to minimize mosquito bites including:

• Staying and sleeping in screened or air-conditioned rooms;

• Covering exposed skin by wearing long-sleeved shirts and long pants;

• Using insect repellents containing DEET, or other agents considered safe in pregnancy; and

• Wearing permethrin-treated clothing and gear.²

If a pregnant woman believes she has been exposed, and especially if fetal microcephaly is suspected, Zika virus testing is available at the CDC Arbovirus Diagnostic Laboratory and a few state health departments. Thus, if needed, you should first contact your state health department to determine availability.

Next: ACOG guidelines on 4 perinatal infections

The Zika virus epidemic and its serious implications for pregnant women dictate that all ob/gyns keep up with relevant WHO, CDC, and American College of Obstetricians and Gynecologists advisories. This latest arbovirus threat is a reminder that healthcare is increasingly global.

For the latest travel advisories from the CDC, visit the CDC site for travel health notices:
wwwnc.cdc.gov/travel/notices

References

1. European Centre for Disease Prevention and Control. Microcephaly in Brazil potentially linked to the Zika virus epidemic: ECDC assesses the risk. November 25, 2015. Available at http://ecdc.europa.eu/en/press/news/_layouts/forms/News_DispForm.aspx?ID=1329&List=8db7286c-fe2d-476c-9133-18ff4cb1b568&Source=http%3A%2F%2Fecdc.europa.eu%2Fen%2FPages%2Fhome.aspx. Accessed January 25, 2016.

2. Zika and pregnancy. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/zika/pregnancy/index.html. Accessed January 17, 2016

3. Fauci AS, Morens DM. Zika virus in the Americas-yet another arbovirus threat. N Engl J Med. 2016 Jan 13. [Epub ahead of print]

4. Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21(2):359–360.

5. Oliveira Melo AS, Malinger G, et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016;47(1):6–7.

6. O’Leary DR, Kuhn S, Kniss KL, et al. Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003-2004. Pediatrics. 2006;117(3):e537–545.

7. Manicklal S, Emery VC, Lazzarotto T, et al. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013;26(1):86–102.

8. Avery GB, Meneses L, Lodge A. The clinical significance of “measurement microcephaly.” Arch Pediatr Adolesc Med. 1972;123:214–217.