SARS-CoV-2 Infection During Pregnancy Creates Immune Changes

Blood samples collected from mothers with COVID-19 and their infants reveal how infection modulates the expression of inflammatory molecules

A recent study of 93 women with COVID-19 and 45 of their infant children who were exposed to SARS-CoV-2 showed that pregnant women infected with the virus produced a pronounced inflammatory response. While the incidence of in utero mother-to-child infection are low, the team saw indications that infection during pregnancy triggers a prenatal immune response that could have implications for long-term infant neurodevelopment and maturation of the immune system.

The study was led by Jae Jung, PhD, director of the Cleveland Clinic Global Center for Pathogen & Human Health Research in collaboration with Karen Nielsen-Saines, MD, of the University of California, Los Angeles. The team studied immune profiles for more than 1,400 cytokines and other inflammatory proteins collected from peripheral and cord blood samples.

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Findings were reported in Cell Reports Medicine.

“We know that pregnancy increases maternal risk for COVID-19, but relatively little is known about the long-term consequences of in utero exposure for infants,” said Dr. Jung. “It is an area needing further study, since generally there is evidence that maternal immune activation in pregnancy is linked to potential long-term neurodevelopmental disorders in early childhood and young adulthood, including autism spectrum disorder and schizophrenia.”

Study background

The mothers and infants studied here were part of the COVID-19 Outcomes in Mother-Infant Pairs Study, a prospective observational cohort of mother-infant pairs diagnosed with SARS-CoV-2 infection in pregnancy in the United States.

The researchers examined maternal blood specimens collected close to the initial detection of SARS-CoV-2 and at different time points throughout pregnancy and delivery. They found that COVID-19 dysregulates maternal immune response. Immune signatures of mothers with asymptomatic disease differ from those with severe disease.

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Most notably, compared to mild or moderate disease, pregnant women with severe COVID-19 exhibited significantly more inflammation and elevated levels of a protein called IFNL1 (interferon lambda 1) and the receptor it binds with, IFNLR1, which plays a critical role in protecting against viruses.

“This increase in interferon lambda signaling may help explain why we see relatively little direct transmission of COVID-19 between mother and baby during the period right before or after birth — what we call vertical transmission,” says Suan-Sin (Jolin) Foo, PhD, a research associate in Dr. Jung’s lab and co-first author on the paper. “More research will be necessary to determine if increased expression of IFNL1 and IFNLR1 does in fact block vertical transmission.”

Cytokine expression in mothers and babies

Despite the lack of evidence for widespread vertical transmission, the researchers found that SARS-CoV-2 infection alters maternal immunity at delivery and that gestational exposure alters infant immunity at birth.

At delivery, the women exhibited dysregulated levels of several cytokines that are associated with pregnancy complications, including MMP7, MDK, ESM1, BGN and CD209. Among infants, prenatal exposure induced the expression of cytokines related to T cells, which are a type of immune cell involved in recognizing and attacking specific antigens. The T cell-associated cytokines include IL33, NFATC3 and CCL21.

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The majority of births within the cohort were healthy, but there was a high incidence of some complications, including preeclampsia and fetal growth restriction. More research will be necessary to understand the extent to which the observed immune changes are related to these clinical outcomes.

“Our findings show that COVID-19 infection during pregnancy leads to distinct immune alterations in mothers and babies, highlighting how important it will be for long-term follow-up after pregnancy to catch and hopefully prevent any unforeseen long-term health conditions related to prenatal infection,” says Dr. Jung.

The study was funded in part by the National Institutes of Health.