Asymptomatic infection with Zika virus underestimated as cause of fetal death

Among nonhuman primates (NHPs) infected with the Zika virus during early gestation, 26% went on to experience stillbirth and miscarriage, in spite of showing few clinical signs of infection, according to a new study published in Nature Medicine. Furthermore, the investigators suggested that asymptomatic Zika infection may be a frequent yet under-recognized cause of miscarriage and stillbirth in humans.

“NHPs are physiologically similar to humans, have extensive parallels in the histology and immunology of the maternal-fetal interface, and recapitulate the clinical course of human ZIKV [Zika virus] infection,” wrote lead author, Dawn M. Dudley, PhD, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI. “Critically, many ZIKV infections in NHPs do not exhibit substantial clinical signs and therefore closely resemble asymptomatic human ZIKV infections.”

In addition to causing sensory defects and fetal brain malformation, Zika virus infection has been found to result in a 5.8% miscarriage risk and a 1.6% stillbirth risk in pregnant mothers infected during the first trimester. However, in reality, this number is probably higher because the estimate is based on studies of women with symptomatic infection.

“There are limitations to the human studies, which rely on symptomatic infections,” says Dr. Dudley. “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.”

In the current study, researchers pooled fetal-demise data of pregnant NHPs infected with Zika strains from Asian and American outbreaks. This pooled data represented six National Primate Research Centers (NPRCs), and teams monitored fetal health via weekly ultrasound, as well as amniocentesis and blood draws.Most of these primates were asymptomatic for the Zika virus infection.

Overall, the investigators observed fetal death in 13 of 50 (26%) animal models, with an additional three animal models experiencing early neonatal death of offspring. In control macaques, rates of fetal demise ranged between 4.0% and 10.9%.

The researchers observed that rates of fetal loss were highest among primates infected with the Zika virus strains from Puerto Rico and Brazil (28.6% and 46.7%, respectively). By comparison, the 6% rate of miscarriage among a sample of previously studied pregnant women from Rio de Janeiro is among the highest rates on record for teratogenic viruses.

Notably, the timing of Zika virus infection predicted fetal demise. Specifically, 37.8% of macaques infected before gestation day 55 experienced fetal demise compared with no cases of fetal or neonatal demise in macaques infected after gestation day 55.

Effects of Zika virus infection were most dramatic in terms of placental damage, with heightened placental calcification the most common finding on ultrasound.

“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,” Dr. Dudley said.

The authors posited that the frequency of miscarriage and stillbirth among Zika-infected mothers is multifactorial and based on gestational age at infection, inoculums, viral strain, maternal age, and other co-infections or comorbidities unrelated to the Zika virus.

“These results, along with recent reports of increased fetal loss in human ZIKV studies, suggest that careful monitoring of fetal loss and stillbirth is warranted,” the authors concluded. “Furthermore, the results of this study suggest that placental pathology may be related to fetal loss, and placental function should be carefully assessed in fetal-demise cases related to ZIKV infection.”