Zika virus could pose a far greater threat to pregnancy than recent studies of miscarriage and stillbirth in human infections have reported.
Researchers at six National Primate Research Centers (NPRCs) combined results from individual studies to find that 26 percent of pregnancies in 50 monkeys infected with Zika virus during the first trimester of pregnancy ended in miscarriage or stillbirth, dwarfing the nearly 8 percent rate found earlier this year by a study of women infected with Zika early in pregnancy. Three more infant monkeys in the new study died soon after birth.
The primate study results were published today in the journal Nature Medicine. Two UW-Madison School of Veterinary Medicine faculty — Ted Golos, a professor of comparative biosciences and obstetrics and gynecology, and Tom Friedrich, a professor of pathobiological sciences — are coauthors of the new study.
Dawn Dudley, lead author of the study, expects the true rate of human miscarriage and stillbirth in Zika infected pregnancies is less than 26 percent, but still much higher than human studies show.
“There are limitations to the human studies, which rely on symptomatic infections,” says Dudley, a scientist in UW-Madison’s Department of Pathology and Laboratory Medicine. “Women get enrolled in the studies because they have Zika symptoms, but we know that up to half of people who have Zika don’t show any symptoms at all. So, the pregnancy studies are probably missing half of the people who have Zika.”
Still more women may have Zika-affected miscarriages before they even know they are pregnant. Others avoid follow-up care for even later-term miscarriages for cultural or other personal reasons.
“You could never account for those women having a miscarriage due to Zika virus infection,” Dudley says.
[quote]We know that up to half of people who have Zika don’t show any symptoms at all. So, the [human] pregnancy studies are probably missing half of the people who have Zika.”[/quote]
In the labs at NPRCs, researchers can control the timing and method of infection in a way those studying human infections cannot, monitoring pregnant monkeys — rhesus macaques at the California, Oregon, Tulane and Wisconsin NPRCs, common marmosets at the Southwest NPRC, and pigtail macaques at the Washington NPRC — to follow the progress of Zika virus in their bodies and into their fetuses and the tissues that support fetal development.
Few of the infected monkeys showed any symptoms of Zika infection (typically a rash and conjunctivitis) despite developing infections that were uniformly passed to their fetuses and the attendant high number of miscarriages and stillbirths.
The researchers found that the Zika virus infections — all using strains of Zika virus from recent Asian and American outbreaks — were particularly hard on the tissues connecting the mother to the developing monkey fetus.
“We’re seeing evidence of damage to the placenta, cell death and areas where the cells are damaged to the point where you don’t have proper function,” says Dudley, whose work was supported by the National Institutes of Health, which also funds the NPRCs. “The placenta provides the blood flow and nutrients to the fetus. If you have problems with that aspect of pregnancy, that can lead to intrauterine growth restriction and poor outcomes – smaller babies all the way to fetal demise if the damage is substantial enough.”
The NPRC researchers decided to pool data from many as-yet-unpublished individual studies last summer during a meeting in Madison of scientists studying HIV and AIDS with monkeys. Dudley, pathology professor David O’Connor and other UW-Madison researchers were comparing notes with Zika investigators from around the country, including study co-author Koen Van Rompay of the University of California, Davis.
“We were sharing our observations that we had seen some of these pregnancies were not going to term,” O’Connor says. “Koen was using the same virus, made by Tom Friedrich, and he was seeing the same thing. Some of their pregnancies were lost. We said, you know, if our groups are seeing the same thing, who else is seeing this?”
A crowd of nearly 40 researchers running studies of NPRC animals with goals like learning about Zika virus and vaccines, Zika virus and the placenta, the way Zika virus’ progression changes in different monkey species, and the safety concerns Zika may cause for oft-transplanted tissue donated by mothers after they give birth all contributed data on their monkey pregnancies. It gave their combined results a weight they would not have carried in smaller pieces.