A groundbreaking study led by researchers at the Cleveland Clinic, published in The EMBO Journal, sheds new light on the potential risks of SARS-CoV-2 infections during pregnancy. The research indicates that even mild and asymptomatic cases can trigger significant inflammatory responses in the developing fetus, challenging the current understanding of vertical transmission.
The study’s findings suggest that vertical transmission of the virus from a pregnant individual to the fetus is more common than previously estimated. Moreover, the pregnant individual’s immunological response to infection may impact the fetus, regardless of whether the virus is transmitted.
To conduct the study, researchers collected samples from the placenta and fetal compartment (the tissues surrounding a fetus while still in the womb) and analyzed them for the presence of inflammatory markers and the virus. They discovered higher instances of the virus in these tissues than traditional nasal swabs could detect and even found small viral proteins had passed through the placenta in the absence of a full infection.
During the early stages of the COVID-19 pandemic, healthcare providers faced significant challenges in determining the best ways to prevent and manage the infection in pregnant patients. OB/GYN Ruth Farrell, MD, and her colleagues at Cleveland Clinic and other major medical centers recognized the need for different medical considerations for pregnant individuals compared to non-pregnant patients. However, many prevention and treatment approaches used for non-pregnant patients lacked sufficient data or were not feasible for pregnant patients.
The delays in understanding the impact of SARS-CoV-2 infection on pregnant patients contributed to disparities that prevented pregnant individuals from accessing the best possible treatment during the pandemic. Dr. Farrell, who also serves as the Vice Chair of Research for Cleveland Clinic’s Obstetrics & Gynecology Institute, worked with clinical colleagues across the Clinical and Translational Science Collaborative (CTSC) of Northern Ohio to develop methods for examining the impact of SARS-CoV-2 infection on pregnant patients.
She then collaborated with Cleveland Clinic maternal-fetal virologists Jolin (Suan Sin) Foo, Ph.D., and Javier (Weiqiang) Chen, Ph.D., from the Infection Biology Program, to determine how the virus affected the immune systems of both mother and child.
When the standard-of-care COVID-19 test is used to detect the virus in newborns (nasal swabs upon birth), it only detects infections in about 2% of children whose mothers tested positive for the virus during pregnancy. However, when Drs. Chen and Foo examined tissues surrounding the newborns while still in the womb, they detected high levels of the virus in over a quarter (26%) of study participants.
The team also found elevated immune and inflammatory responses affecting approximately 66% of study participants. Dr. Foo had previously shown that severe SARS-CoV-2 infections during pregnancy led to elevated levels of fetal inflammation. However, few had asked whether asymptomatic or mild infections had the same effect. Now, the team had their answer, but it raised even more questions.
“Even though we only saw vertical transmission of the full virus infection a quarter of the time, we saw strong immune and inflammatory responses in over two-thirds of the cases,” Dr. Foo explains. “It was clear that even when the fetuses were not technically infected, they were still being impacted by their mothers’ viral infection. But we weren’t quite sure how.”
Elevated levels of inflammation during pregnancy, in COVID-19 and other conditions, can have negative impacts on the offspring long after birth. Further research is needed to define how inflammation affects children in the long term.
Dr. Chen noted that the SARS-CoV-2 virus has a protein called ORF8 that physically resembles a human immune protein called immunoglobulin G, which passes through the placenta from mother-to-fetus during development. He wondered whether the viral protein could also pass through the placenta’s defenses to cause inflammation in the fetal compartment.
Drs. Foo and Chen, alongside co-first authors Tamiris Azamor, Ph.D., and Débora Familiar-Macedo, Ph.D. (a former and current postdoctoral researcher, respectively, in Dr. Foo’s lab), were able to prove that the virus-made ORF8 did indeed pass through the placenta into the fetus. ORF8 then bound to immune proteins and turned on a process called the complementary immune response.
“Our findings challenge the currently accepted definition of vertical transmission,” Dr. Chen says. “We have shown that it is indeed possible for only a small part of a virus to slip through and affect a pregnancy.”
Dr. Foo adds, “I hope our findings will serve as guidance for healthcare practitioners, researchers, and policymakers alike on further research into vertical transmission and long-term care. We’ve shown that the misconception that uninfected babies born from infected mothers are fine is sometimes just that: a misconception. Pregnancy is such a vulnerable nine-month period where any change from the norm can cause long-term impacts on the baby. We need to work more closely with these individuals to understand their unique healthcare needs during public health crises. It’s the only way to make sure they receive the care they need.”
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1. Source: Coherent Market Insights, Public sources, Desk research
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