Fetal abnormalities -- including central nervous system abnormalities -- have been observed in 29% of a cohort of pregnant women confirmed to have Zika virus infection, an international team of researchers is reporting.

Investigators did not see similar complications in pregnant women without Zika infection, according to Karin Nielsen-Saines, MD, of the David Geffen School of Medicine in Los Angeles, and colleagues in the U.S. and Brazil.

The findings, reported online in the New England Journal of Medicine, appear to remove any doubt that the virus can cause neurological complications in unborn infants.

Meanwhile, a separate laboratory-based study, reported online in Cell Stem Cell, shows that the Zika virus can infect the progenitor cells that give rise to the cortex, leading to slowed and abnormal growth, as well as cell death.

In the experiments, the virus infected 90% of the human cortical neural progenitor cells, many of which died and released new copies of the virus.

The research suggests a mechanism that could explain the sorts of outcomes seen in the study by Nielsen-Saines and colleagues and in patients in Brazil.

"It's very telling that the cells that form the cortex are potentially susceptible to the virus, and their growth could be disrupted by the virus," commented study author Guo-Li Ming, MD, PhD, of Johns Hopkins University in Baltimore.

The cells involved eventually differentiate and form both neurons and glial cells that provide the scaffolding of the brain. If the pool of such cells is reduced, Ming told MedPage Today, "you can imagine" that the downstream effects on the developing brain would be widespread.



She cautioned that the study did not show that the virus in a living body can get into the brain.
Taken together, the two studies fill in some of the major gaps in the Zika story, according to William Dobyns, MD, of Seattle Children's Hospital.

Dobyns said it has been clear to experts for some time -- based on brain scans of some of the affected infants in Brazil -- that something unusual is occurring.

The images, he told MedPage Today, show an "extremely rare" pattern of abnormalities.

"Over the last 30 years, I've seen that pattern four or five times," he said. "Now suddenly, over the last month I've seen 15 (brain scans), all with the same pattern, all from northern Brazil."

The paper by Ming and colleagues, he said, shows that Zika virus has a "tropism" to human cortical neural progenitor cells.
Importantly, he said, it also describes the type of developmental damage that would be expected to give rise to the abnormalities seen in the Brazilian imaging -- small brains, with expanded fluid-filled gaps, and areas of calcification indicating dead cells, as well as an unusually smooth cortex.

Zika is a mosquito-borne flavivirus, a class of pathogens that has not been known to cause birth defects. But other infections -- such as cytomegalovirus and toxoplasmosis -- do cause such complications, according to Dee Quinn, MS, of the University of Arizona and a spokesperson for the nonprofit Organization of Teratology Information Specialists.

Indeed, Quinn told MedPage Today, the complications that are being seen in Brazil -- such things as enlarged fluid-filled ventricles, polymicrogyria (in which the peaks and valleys of the brain are flattened out), and small areas of dead cells -- are very similar to what is observed after pregnant women are exposed to the other infections.

Dobyns added that the pattern of abnormalities is very close to what is seen with cytomegalovirus, with perhaps some subtle differences.

The study by Nielsen-Saines and colleagues is the third "smoking gun" that helps make the case that Zika is causing the brain malformations, Dobyns said.

Details of NEJM Study
Nielsen-Saines and colleagues enrolled 88 pregnant Brazilian women who suffered a rash within the 5 days before.
enrollment. While the symptoms of Zika virus are usually mild, when they are present at all, they include a maculopapular rash, as well as fever, headache, and red eyes.

The investigators tested the women's blood and urine for Zika virus using reverse transcriptase polymerase chain reaction methods. Seventy-two of them, at between 5 and 38 weeks of gestation, tested positive for Zika in blood, urine, or both, and the remaining 16 were negative.

Women who were positive for Zika were more likely than those who were negative for the virus to have a rash that was maculopapular (44% compared with 12%), conjunctival involvement (58% versus13%), and lymphadenopathy (40% compared with 7%). The differences were significant at P=0.02, P=0.002, and P=0.02, respectively.

The researchers examined the fetuses, using Doppler ultrasound, in 42 of the Zika-positive women and in all 16 of those who were negative for the virus.

They detected fetal abnormalities in 12 of the tested Zika-positive women (or 29%); adverse findings included:

In utero growth restriction with or without microcephaly in five fetuses
Ventricular calcifications or other central nervous system lesions in seven fetuses
Abnormal amniotic fluid content or cerebral, umbilical, placental artery flow in seven fetuses

As well, two fetuses died at 36 and 38 weeks of gestation; the mothers had been infected at 25 and 32 weeks. Ultrasound findings have been confirmed in the eight Zika-positive women who have delivered their babies, Nielsen-Saines and colleagues noted.

The timing of the infections is an important question, Dobyns noted, since the paper by Ming and colleagues suggests that infection in the late first trimester or early second trimester is likely to have the most severe consequences. Nielsen-Saines and colleagues reported, however, that the Zika infections occurred from 6 to 35 weeks of gestation, while the mothers whose fetuses had abnormalities were infected from 8 weeks to 35 weeks of gestation.

Indeed, four of the mothers with abnormal fetuses were infected in the first trimester, six in the second trimester, and two in the third, they found. Previous research has shown that Zika virus can be detected in the amniotic fluid of pregnant women, showing it could cross the placental barriers. As well, the virus has been found in the brain tissue of a fetus whose European mother had requested an abortion after in utero testing showed severe microcephaly and other signs of degeneration of the brain.

The extent of the risk of microcephaly or central nervous system malformations remains unclear. The World Health Organization's March 4 situation report notes that only Brazil and French Polynesia have seen such complications, although some 52 countries worldwide currently have or have had a Zika outbreak since 2007.

In Brazil, the agency said, some 5,909 suspected cases of microcephaly and/or central nervous system malformation were reported between Oct. 22, 2015 and Feb. 27, 2016. The number is markedly higher than the average of 163 microcephaly cases annually recorded from 2001 through 2014.

Indeed, four of the mothers with abnormal fetuses were infected in the first trimester, six in the second trimester, and two in the third, they found. Previous research has shown that Zika virus can be detected in the amniotic fluid of pregnant women, showing it could cross the placental barriers. As well, the virus has been found in the brain tissue of a fetus whose European mother had requested an abortion after in utero testing showed severe microcephaly and other signs of degeneration of the brain.

The extent of the risk of microcephaly or central nervous system malformations remains unclear. The World Health Organization's March 4 situation report notes that only Brazil and French Polynesia have seen such complications, although some 52 countries worldwide currently have or have had a Zika outbreak since 2007.

In Brazil, the agency said, some 5,909 suspected cases of microcephaly and/or central nervous system malformation were reported between Oct. 22, 2015 and Feb. 27, 2016. The number is markedly higher than the average of 163 microcephaly cases annually recorded from 2001 through 2014.

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