In a recent study posted to the bioRxiv* pre-print server, a team of researchers evaluated inflammatory cytokine profiles of mothers infected with coronavirus disease 2019 (COVID-19) during pregnancy and their infants.
While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-induced inflammatory cytokine production in adults is well characterized, relatively little is known about the infant cytokine signatures in pregnancies affected by SARS-CoV-2.
Although there is accumulating clinical evidence that a mother infected with SARS-CoV-2 during pregnancy usually does not transmit the infection to her infant, immune activation and inflammation response to SARS-CoV-2 can potentially impair the developing fetuses’ growth, particularly its brain development and cognitive function later in life.
For this study, the researchers hypothesized that when compared to control group pregnancies (patients negative for SARS-CoV-2 at delivery), SARS-CoV-2-positive mothers and their infants show substantial alterations in their inflammatory cytokines, which vary with the gestational timing of maternal COVID-19.
They enrolled mother-infant dyads from the Boston Medical Center obstetric prenatal clinics, Labor and Delivery, the Postpartum Unit, and Newborn Intensive Care Unit for their cohort study between July 2020 and June 2021. These patients were at least 18 years of age, had a positive SARS-CoV-2 infection at any point during pregnancy, a viable singleton gestation pregnancy, and were English or Spanish-speaking women. The control group of females was enrolled between January and April 2021, were not COVID-19 infected throughout their pregnancy, and were unvaccinated for SARS-CoV-2.
In total, 31 SARS-CoV-2-positive mother-infant dyads (COVID-19 cohort) and 29 SARS-CoV-2-negative mother-infant dyads (Control) were examined during the study. Serum samples (maternal blood and cord blood/infant blood) from the time of delivery were evaluated using a 13-plex cytokine assay, which analyzed several cytokines such as IP-10, IL-6, TNF-α, IFN- α1, and IL-10. In particular, the researchers evaluated cytokine-level changes relative to the gestational timing of maternal SARS-CoV-2 infection.
The study reported an altered profile of cytokines such as IP-10, IL-6, and IL-8 in the COVID-19 cohort. These alterations were identified even among the Early COVID-19 cohort, suggesting persistent elevation of inflammatory cytokines in maternal and neonatal circulation months after initial maternal SARS-CoV-2 infection.
It is worth noting that the percentage of patients infected with COVID-19 varied with gestation timing. Consequently, three patients (9.7%) were infected in the first trimester, 18 patients (58.1%) in the second trimester, and 10 patients (32.3%) in the third trimester. The COVID-19 cohort also contained 28 (90.3%) patients with COVID-19 symptoms anytime during their pregnancy, of which 6.6% even required hospitalization. Infants born to mothers of the COVID-19 cohort were not diagnosed with SARS-CoV-2 infection within 30 days of delivery.
In both maternal and infant blood, there were significantly high levels of IP-10 in the COVID-19 cohort, compared to the Control group. While these elevations were noted in both Early COVID and Late COVID groups, IP-10 maternal levels were significantly high in the Late COVID group, and the highest IP-10 infant blood levels were observed in Early COVID pregnancies. The Early COVID cohort also had the highest IL-6 serum elevations for maternal and infant samples. In addition, IFN-α1 showed a trend in elevation among COVID maternal samples of the Early COVID cohort. However, IL-8 was notably higher in the infant COVID cohort compared to the maternal COVID cohort. As expected, there was no correlation between maternal and infant cytokine levels among dyads.
Some of the study findings were expected, such as the elevated maternal serum levels of IP-10 and IL-6, which are primary components of the COVID-19 cytokine storm, and 90% of the maternal COVID-19 cohort had active COVID-19 rather than asymptomatic carrier status. Further, these findings suggest that these cytokines persist from weeks to months after COVID-19 onset as only 1% of mothers had active disease symptoms at the time of serum sample collection.
The maternal and infant cytokine profiles for IP-10, IL-6, and IL-8 are different, suggesting that elevated infant cytokine levels result from an independent and active fetal immune response to maternal SARS-CoV-2 during pregnancy, and are not passively transferred from the mother to the fetal circulation.
The study findings suggest that both SARS-CoV-2-infected mothers and their fetuses have increased levels of inflammatory cytokines throughout gestation, which may potentially impact fetus health in the long term. Therefore, the authors emphasize follow-up for infants from pregnancies affected by maternal SARS-CoV-2. To conclude, future studies should attempt to more extensively characterize the driving mechanisms and developmental impact of the cytokine alterations identified in this study using larger patient cohorts and more effective pre-clinical models.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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