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: A new study from Brazil shows a very high rate of fetal central nervous system abnormalities with both first-trimester and second-trimester exposure to the Zika virus, compared with data from the United States and other areas in the world where the rate of fetal abnormalities has been lower.

SOURCE: Brasil P, Pereira JP Jr, Moreira ME, et al. Zika virus in pregnant women in Rio de Janeiro. N Engl J Med 2016;375:2321-2334.

Last spring, I wrote a special feature in OB/GYN Clinical Alert dedicated to the Zika virus. Since that time, new information is available to help us understand the spectrum of abnormalities this virus can cause in the fetus. Brazil garnered the earliest attention after the association between the Zika virus and microcephaly surfaced. New information from Rio de Janeiro again has shown that microcephaly represents only one late component of a multifaceted process.

Between September 2015 and May 2016, Brasil et al studied women with signs of Zika virus infection (descending pruritic rash, fever, arthralgia, conjunctivitis) presenting for care in a large clinic in Rio de Janeiro. They compared 125 patients who tested positive for Zika virus (RT-ZIKV) by reverse transcriptase polymerase chain reaction (PCR) within five days of symptoms with 51 patients who tested negative after symptoms.

Forty-two percent of Zika-positive and 3% of Zika-negative patients were positive for chikungunya. Fetal death occurred in 7.2% of Zika-positive and in 6% of Zika-negative patients. Overall, adverse outcomes were noted in 46% of Zika-positive patients, with 42% having either obvious clinical or image-diagnosed central nervous system (CNS) abnormalities. Interestingly, brain abnormalities occurred almost equally among those exposed in the first trimester (55%) and second trimester (52%), with 29% occurring after third-trimester exposure. The emergency cesarean section rate for fetal distress was much higher in the Zika-positive patients (23.5% vs. 2.5%).

COMMENTARY

The initial reports from Brazil linking Zika with microcephaly sent chills around the world, especially in areas in which the Zika-bearing mosquito, Aedes aegypti and Aedes albopictus, are indigenous. The population in the featured study represented the perfect storm. The women were all symptomatic and lived in an area where the virus had already been known to cause serious fetal CNS damage — and the results bore this out. The biggest surprise was that the devastating effects happened in equal amounts (about 50%) after both first- and second-trimester exposure and occurred even in one out of three patients with third-trimester exposure.

It is important to note that the experience from other areas in the world does not mirror the results from this Zika hot spot. For example, CDC data from 442 Zika-positive women in the United States and Hawaii have shown a 6% chance of birth defects (mostly CNS), with a 4% overall incidence of microcephaly.1 Unpublished data from Zika-positive women in Puerto Rico and Columbia are now showing similar results, with less than a 10% chance of CNS abnormalities, intrauterine growth restriction, or fetal demise, with, again, mostly first-trimester exposure.

New insight from expanded experience:

  1. Viremia in most patients is short-lived, generally being gone by nine days. However, the CDC has noted rare pregnant patients to be PCR-positive for Zika up to 50 days. The virus can be found in urine up to 14 days. After this time, one relies on the presence of Zika IgM antibodies for the diagnosis. A troublesome finding is that infected males can have the virus in their semen in huge concentrations for up to 62 days.
  2. The well-publicized finding of microcephaly represents only the tip of the iceberg. This finding in infected cases in Brazil and the Polynesian islands provided a dramatic awakening of the effects of Zika, but it is a late development in a process that can cause an assortment of abnormalities such as ventriculomegaly, cortical thinning, generalized brain shrinkage, and dysgenesis of midline structures (corpus callosum, cerebellar vermis, and brainstem).2 Periventricular calcifications are common. The virus interferes with the ladder-like progression upward of neuronal development, stopping the migration at the white matter/gray matter border and leaving the fetus with a shrunken brain and, ultimately, a small calvarium. A few cases of brain abnormalities have been accompanied by arthrogryposis, probably because of diminished fetal movement. Virtually all the early signs of Zika can be diagnosed with 3-D ultrasound techniques and MRI.
  3. Eighty percent of Zika-positive patients do not have symptoms and some studies suggest that this has no bearing on the chance of CNS abnormalities. The featured study showed that there was a 13% incidence of adverse outcome in symptomatic patients despite negative Zika testing, suggesting that other viruses such as chikungunya could be responsible. Superimposed infection might also have been responsible for the surprisingly high rate of abnormalities in this Brazilian population.
  4. There is no currently available treatment for Zika. Inactivated virus (Zika purified inactivated virus) vaccine and a DNA-based vaccine are now being tested in Phase I trials but there is no timeline for their availability. Most importantly, every effort should be directed toward making a timely definitive fetal diagnosis to enable parents to weigh their options as early in pregnancy as possible.
  5. Prevention: N, N dimethyl meta toluamide (DEET) is an effective skin preventive and appears to be safe in pregnancy, as well as permethrin for spraying of clothes.3 Eliminating standing water in vulnerable communities is essential, as well as aerial spraying.

Some suggestions by the CDC and/or Society for Maternal-Fetal Medicine:4,5

  1. Pregnant women or those contemplating pregnancy should avoid travel to high-risk areas noted in the CDC website.
  2. Male partners traveling to these areas either should avoid intercourse or use protection for six months after returning. Women with or without symptoms would benefit from blood testing with Zika RT-PCR within the first five days of possible exposure, blood and urine RT-PCR testing between 5 and 12 days of exposure, and serum IgM for Zika (Elisa) after that time.
  3. Ultrasound exams should be scheduled every 2-4 weeks in those testing positive. Since microcephaly is a late sign, the exam should include a detailed evaluation of the intracranial anatomy (preferably with the help of 3-D volume acquisition). A finding of concern can then be backed up with MRI.

REFERENCES

  1. Honein MA, Dawson AL, Petersen EE, et al. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 2017;317:59-68.
  2. Oliveira Melo AS, Malinger G, Ximenes R, et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: Tip of the iceberg? Ultrasound Obstet Gynecol 2016;47:6-7.
  3. Wylie BJ, Hauptman M, Woolf AD, Goldman RH. Insect repellants during pregnancy in the era of the Zika virus. Obstet Gynecol 2016;128:1111-1115.
  4. Meaney-Delman D, Rasmussen SA, Staples JE, et al. Zika virus and pregnancy. What obstetric health care providers need to know. Obstet Gynecol 2016;127:642-648.
  5. Society for Maternal-Fetal Medicine (SMFM) Publications Committee. Ultrasound screening for fetal microcephaly following Zika virus exposure. Am J Obstet Gynecol 2016;214:82-84.