Scientists today moved two steps closer to proving a link between birth defects and Zika virus, with a clinic-based team documenting outcomes in ill Brazilian pregnant women, many of whom delivered babies with health problems, and a lab-based group showing how the virus likely kills or disrupts developing fetal brain cells.
The investigation involving pregnant women in Rio de Janeiro was a cohort study, which along with studies that are of the case-control design, is a gold standard for proving an association between an exposure and a disease or outcome. A team from Brazil's Oswaldo Cruz Institute and the University of California, Los Angeles, published their findings today in the New England Journal of Medicine.
Meanwhile, a research team based at Johns Hopkins and involving two other universities published the results of their lab experiments with different types of neural cells today in the journal Cell Stem Cell.
Cohort study shows range of fetal development problems
In the first study, researchers followed 88 pregnant women who sought care for a rashlike illness at the Oswaldo Cruz clinic in Rio between September 2015 and January 2016. Of the total, 72 tested positive for Zika virus on the basis of blood tests, urine tests, or both. The timing of their infections ranged from 5 weeks to 38 weeks gestation.
The women were of all socioeconomic levels and lived in a wide range of neighborhoods across the city. More than half reported similar illnesses in family members, and more than half reported their acute infection during the second pregnancy trimester.
Fetal ultrasounds were done in 42 of the women who tested positive for Zika virus and in all 16 whose test results were negative. Abnormalities were detected in 12 (29%) of the women who tested positive for the virus but in none of those who tested negative.
Researchers found a range of abnormal findings in the 12 women with abnormal fetal ultrasounds, including fetal death (2 fetuses), growth restriction with or without microcephaly (5), ventricular calcifications or other central nervous system lesions (7), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7).
So far, 8 of the 58 women who underwent fetal ultrasound have delivered their babies and their respective ultrasound findings have been confirmed. Six were live births and two were stillbirths (the latter being the fetal deaths on ultrasound). Two babies with normal ultrasound findings had a normal physical exam at birth. One baby was born with severe microcephaly. Of the three other births so far, one baby was delivered early by cesarean section owing to severe growth restriction and other problems, one had suspected neurologic findings but is now doing well, and one was small for gestational age and is in the neonatal intensive care unit.
Investigators said their ultrasound findings show serious and frequent problems with fetal and central nervous system development, affecting 29% of the 42 women who had fetal ultrasounds.
They pointed out that problems were seen in the fetuses of women regardless of the week of gestation at infection. Central nervous system problems occurred with infection as late as 27 weeks gestation; placental-insufficiency problems skewed toward cases where infection occurred in later gestational stages. The team also noted that microcephaly in the cohort was part of an overall pattern of restricted fetal growth rather than being an isolated finding.
Though the size of the control group of 16 women who were negative for Zika virus was small, they lived in the same geographic area as the infected women and likely had the same type of environmental exposure, the team wrote. They concluded that the study adds more support for a link between maternal Zika infection and fetal and placental problems, similar to other viruses known to cause problems in newborns.
Lab study hints at possible damage dynamics
In the Johns Hopkins study, researchers used lab-grown human stem cells to study early human brain development with a goal of examining how Zika virus might lead to microcephaly. They compared the virus's effect on cortical neural progenitor cells with its effect on two other cell types: induced pluripotent stem cells and immature neurons.
The authors exposed the cells to Zika virus, then analyzed their genetic expression. Three days after exposure, 90% of cortical neural progenitor cells—found to be the most vulnerable ones—were infected and were producing new copies of the virus, according to the report.
Many of the cells died, and others showed changes in gene expression that impaired cell division.
Johns Hopkins said a press release today that the experiments were done in less than a month, reflecting the deep concerns about the nature of suspected Zika virus complications. A Florida State University scientist reached out to two of the university's experts in stem cells that related to early brain development. The gene expression patterns were then analyzed by a lab group at Emory University.
Guo-Ii Ming, MD, PhD, a Johns Hopkins neuroscientist, said in the statement, "While this study doesn't definitely prove that Zika virus causes microcephaly, 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."
The team is using the cells to learn more about the impact of Zika virus on the fetal cortex and says the cortical neural progenitor cells can probably also be useful in screening possible new therapies.
Mar 4 N Engl J Med report
Mar 4 Cell Stem Cell study
Mar 4 Johns Hopkins press release