New UCLA-led research finds that severe COVID-19 illness during pregnancy triggers an inflammatory "cascade" that may lead to damage associated with the disease -- and which in turn may alter the infants' own immune system.
The findings, published in the peer-reviewed journal Cell Reports Medicine, may explain why COVID-19 during pregnancy can cause severe, damaging disease, said Dr. Karin Nielsen, professor of pediatrics in the division of infectious diseases at the David Geffen School of Medicine at UCLA and the study’s senior author. These findings also demonstrate the impact COVID-19 can have on infants born to women who had the infection during pregnancy, even when the infants are not infected with the virus.
"It's important to highlight that this is different from other infections women may have during pregnancy that are transmitted to babies, as in the case of congenital Zika for example," Nielsen said. "In that setting, the damage is caused by the virus that passes on from the mother to the baby. The babies in our study were not infected with SARS CoV-2, the virus responsible for COVID-19 - they were all tested, and were negative."
"Any problematic repercussions to the baby would derive from exposure to severe maternal inflammation during pregnancy, and not necessarily from infection with the virus," she added.
The researchers focused on cellular proteins called cytokines, which are important components of the immune system. Cytokines are secreted by immune cells and essentially call up white blood cells to respond to an infection or injury. Chemokines are a type of cytokine that guide white blood cells to the site in need of repair. Levels of these proteins are in balance in healthy bodies, but in the presence of COVID-19, some cytokines are triggered and others silenced in a process called upregulation or downregulation.
The researchers tested 93 mothers infected with COVID-19 and 45 of their infants at day 1 that were exposed in the womb using a novel technology known as next generation sequencing (NGS)-based Olink proteomic profiling. This NGS technology enabled screening of nearly 1,500 cytokines, thus identifying alterations in immune system proteins and pathways.
They found that severe COVID-19 appears to rewire the immune systems in mothers and their newborns. In mothers with severe disease, COVID-19 upregulated and downregulated specific cytokines during pregnancy and delivery. These inflammatory "pathways," as they are called, are associated with liver and heart disease. In addition, infants born to mothers with severe COVID-19 had inflammatory profiles, identified by the presence of specific cytokines and chemokines, which were different from those normally found in newborns. These altered cytokine levels are usually present in infants with respiratory problems and, in some cases, poor neurodevelopment. The researchers did not find these immune alterations in infants born to mothers who were infected but asymptomatic or who had mild to moderate COVID-19 disease.
"For this reason, we are also following the mothers alongside with their babies and measuring the expression of these cytokines at regular intervals post-delivery to see how these are behaving, in addition to gathering information on their overall health," Nielsen said.
The researchers caution this was an observational study, so other factors they did not examine may have caused these effects. Also, UCLA receives many people with severe illness who are referred by other hospitals - some of the patients studied had more critical cases. The authors note that more research is needed to further characterize the clinical implication of these findings.
Additional study authors are Dr. Mary Catherine Cambou, Dr. Thalia Mok, Dr. Viviana Fajardo, Trevon Fuller, Tara Kerin, Dr. Jenny Mei, Dr. Debika Bhattacharya, Jessica Cranston, Dr. Grace Aldrovandi, Dr. Nicole Tobin, Deisy Contreras, Francisco Ibarrondo, Dr. Otto Yang, Shangxin Yang, Omai Garner, Ruth Cortado, Dr. Yvonne Bryson, Dr. Carla Janzen, Shubhamoy Ghosh, Dr. Sherin Devaskar, Vaithilingaraja Arumugaswami, and Dr. Rashmi Rao of UCLA; Suan-Sin Foo, Kyle Jung, Weiqiang Chen and Jae Jung of Cleveland Clinic; and others from Instituto Nacional de Infectologia Evandro Chagas and Instituto Fernades Figueira in Brazil, Georgetown University, and Cedars-Sinai Medical Center.
This work was partly supported by the UCLA W. M. Keck Foundation COVID 19 Research Award Program, several NIH awards, Korea Research Institute of Bioscience and Biotechnology Research Initiative Program, and the Simons Foundation Autism Research Initiative.
