The New York Times, February 8, 2016
The Zika virus has quickly gained Ebola-level notoriety as it has spread through the Western Hemisphere in recent months. Researchers in Brazil, where it was first detected in May, have linked infections in pregnant women to a condition known as microcephaly: infants born with undersize heads.
Where birth defects are concerned, however, the Zika virus is far from unique. A number of other viruses, such as rubella and cytomegalovirus, pose a serious risk during pregnancy. Researchers have uncovered some important clues about how those pathogens injure fetuses — findings that are now helping to guide research into the potential link between Zika and microcephaly.
“I think we’ll discover a lot of parallels,” said Dr. Mark R. Schleiss, the director of pediatric infectious diseases and immunology at the University of Minnesota Medical School.
The risk that viruses pose during pregnancy came to light in the mid-1900s, when outbreaks of rubella, or German measles, led to waves of birth defects, including microcephaly, cataracts and deformed hearts and livers.
The number of infants affected was staggering. In an epidemic in Philadelphia in 1965, 1 percent of all babies were born with congenital rubella syndrome, which can also cause deafness, developmental disability, low birth weight and seizures.
Because of vaccinations, such devastation is now rare in the United States and a number of other countries. “I’m 52, and I’ve seen one case of congenital rubella syndrome,” said Dr. David W. Kimberlin, a professor of pediatrics at the University of Alabama at Birmingham.
But the virus is still a grave threat in developing countries. Worldwide, more than 100,000 children are born each year with congenital rubella syndrome.
Other viruses have also been identified as causing birth defects. Cytomegalovirus, for example, contributes to at least 5,000 birth defects each year in the United States alone.
Doctors do not systematically screen for cytomegalovirus and other well-known viral threats, and it can be difficult to pin down the link to birth defects. Unless the viruses strike in sudden outbreaks, their effects can be hard to tease out from other causes of birth defects.
As a result, the true scale of virus-caused birth defects remains unknown.
“I don’t think we have a good estimate of the number that are due to congenital infections,” said Peggy Honein, an epidemiologist at the Centers for Disease Control and Prevention.
Understanding how certain viruses infect fetuses has been a major challenge for scientists. Cytomegalovirus infects only humans: To study the disease in, say, guinea pigs, researchers have had to use a species of cytomegalovirus that infects only guinea pigs.
Recently, however, scientists have figured out how to grow human cytomegalovirus in human cell cultures. These studies have helped to show that when a pregnant woman is infected by the virus, it does not immediately strike the fetus.
Lenore Pereira, a virologist at the University of California, San Francisco, and other researchers have documented a long series of steps that the virus must take to complete this journey. “This can take weeks,” she said.
Cytomegalvirus first infects the wall of the uterus. Then it moves to the placenta — but the virus attacks only certain types of placental cells.
From the placenta, the virus can travel into the amniotic sac, and then to the fetus itself.
If cytomegalovirus reaches the fetus early in development, the infection can cause serious harm, especially to the brain. The fetus’s immune system has barely developed at that point, while the brain is already growing rapidly.
Once cytomegalovirus enters the fetal brain, it waits for a few days. Only after the brain has begun to mature do the viruses start multiplying inside stem cells that will later give rise to neurons.
The process seems suspiciously well timed to some researchers. “It might be a strategy not to kill the host,” said Dr. Dana G. Wolf, the director of the Clinical Virology Unit at Hadassah Hebrew University Medical Center in Jerusalem.
In Brazil, scientists are comparing the brain damage in babies perhaps caused by the Zika virus with what is known of the effects of cytomegalovirus and rubella. “Some findings in our patients are strikingly different,” said Lavinia Schuler-Faccini of the Federal University of Rio Grande do Sul.
Zika virus appears to cause more widespread damage in the brain, Dr. Schuler-Faccini said. She has observed that the surface of some of the microcephalic brains is unusually smooth — a symptom not seen in infections of rubella or cytomegalovirus.
She hypothesized that the virus infected fetuses very early in development, creating a bigger disruption to cells as they give rise to the brain.
Dr. Gil G. Mor, the director of reproductive sciences at Yale University School of Medicine, said that scientists should not rule out the possibility that the Zika virus caused damage without ever infecting fetuses.
He and his colleagues have found evidence for such indirect damage by infecting pregnant mice with herpeslike viruses. The viruses never got past the placenta to infect the fetus — yet somehow the mothers gave birth to pups with brain deformities.
When certain viruses attack the placenta, Dr. Mor said, they may spark a powerful immune response from the mother. Inflammation-triggering molecules spread from the infection, and some may end up in the fetus. Its tissues may then swell and become damaged, and may even die off.
Dr. Mor said he suspected that the brains of fetuses could be especially vulnerable to this kind of bystander damage early in development. “Whatever comes from Mom goes to the brain, good or bad,” he said.
As a result, Dr. Mor added, researchers looking for proof that Zika viruses cause birth defects should not limit their search to viruses in children with deformities. “You may look and not find it,” he said.
Koen Van Rompay, a virologist at the University of California, Davis, is also looking for Zika virus — but not in humans. Instead, he and his colleagues are preparing to infect pregnant monkeys to see how their offspring are affected.
If they discover birth defects, they will investigate whether the virus is directly invading the fetuses or causing a harmful immune response in the mother.
“Let’s be on the safe side and keep both sides open,” Dr. Van Rompay said.
The lessons that scientists have gained from viruses like rubella and cytomegalovirus could also point to potential treatments.
“If we understand how the virus infects cells, we can come up with ways to suppress it,” Dr. Pereira said. Studies of cytomegalovirus, for example, suggest that it may be possible to block birth defects by injecting a mother with antibodies before the virus reaches the fetus.
Dr. Mor said that the attention now focused on the Zika virus may make scientists appreciate just how much viruses could affect fetal health.
Along with deformities that are present at birth, these infections can also have effects on children that emerge later. Children as old as 8, for example, can go deaf from cytomegalovirus infections their mothers had during pregnancy.
The effects of a mother’s response to viruses may also be of enormous importance, but right now, scientists understand them much less. Some studies have hinted that viral infection during fetal development can raise a child’s risk of developing autism or schizophrenia. It will take many years, and much more evidence, to evaluate those links.
“We cannot ignore infections during pregnancies,” Dr. Mor said. “This is more than Zika.”
Copyright 2016 The New York Times Company. Reprinted with permission.