Preeclampsia and COVID-19: the Role of Inflammasome Activation.

PURPOSE OF REVIEW: It is well established that controlled immune activation and balance is critical for women's reproductive health and successful pregnancy outcomes. Research in recent decades in both clinical and animal studies has demonstrated that aberrant immune activation and inflammation play a role in the development and progression of women's reproductive health and pregnancy-related disorders. Inflammasomes are multi-protein cytoplasmic complexes that mediate immune activation. In this review, we summarize current knowledge on the role of inflammasome activation in pregnancy-related disorders. RECENT FINDINGS: Increased activation of inflammasome is associated with multiple women's health reproductive disorders and pregnancy-associated disorders, including preeclampsia (PreE). Inflammasome activation is also associated with the novel coronavirus disease 2019 (COVID-19) disease caused by the SARS-Cov-2 virus. We and others have observed a positive association between increased PreE incidences with the onset of the COVID-19 pandemic. Here, we present our recent data indicating increased inflammasome activation, represented by caspase-1 activity, in women with COVID-19 and PreE compared to normotensive pregnant women COVID-19. The role of inflammation in pregnancy-related disorders is an area of intense research interest. With the onset of the COVID-19 pandemic and the associated increase in PreE observed clinically, there is a greater need to identify mechanisms of pathophysiology and targets to treat this maternal disorder. Inflammasome activation is associated with PreE and COVID-19 infection and may hold therapeutic potential to improve outcomes associated with PreE and curb the morbidity attributed to PreE.

COVID-19 not Hypertension or Diabetes increases the risk of Preeclampsia among a high-risk population

Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has been associated with greater morbidity and increased mortality in certain populations, such as those with chronic medical conditions, the elderly, and pregnant women. COVID-19 infection in pregnancy is associated with greater rates of hospitalization, ICU admission, need for mechanical ventilation, and death. Pregnancy related morbidity such as preterm delivery, fetal growth restriction, preeclampsia and stillbirth are increased in mothers with COVID-19 illness. To determine if COVID-19 infection during pregnancy increased the risk of preeclampsia in a population of women with increased risk factors for preeclampsia. Study DESIGN We present a prospective observational matched case-control study of the first 100 deliveries with nasopharyngeal swab PCR confirmed SARS-CoV2 at the University of Mississippi Medical Center's Winfred L. Wiser Hospital for Women & Infants. Specifically, we investigated the maternal and neonatal outcomes in a high-risk population of Mississippi pregnant women. COVID-19 infection during pregnancy is associated with greater rates of developing preeclampsia in mothers with pre-existing diabetes or chronic hypertension. Main OUTCOME MEASURES Results Among women with COVID-19, the severity of symptoms was associated with the incidence of preeclampsia, but not with pre-existing diabetes or hypertension. Women with more severe symptoms were more likely to delivery pre-term (p=0.006) and had smaller babies (p=0.04). There were no significant differences in maternal demographic characteristics between matched groups. After adjusting for diabetes, hypertensive women with COVID-19 had an increased risk of preeclampsia aOR4.3 [95%CI 1.5, 12.4] compared to non-hypertensive women with COVID-19. After adjusting for hypertension, women with diabetes and COVID-19 had an increased risk of preeclampsia aOR3.9 [95%CI 1.2, 12.5]. This relationship was not seen among women without COVID-19. Conclusion Women with COVID-19 and severe symptoms were at a higher risk to delivery preterm. For women who had pre-existing diabetes or hypertension, the risk of developing PreE was only increased if they were also diagnosed with COVID-19, suggesting that in our population of women the risk of PreE is not associated with pre-existing diabetes or hypertension.

COVID-19 Not Hypertension or Diabetes Increases the Risk of Preeclampsia among a High-Risk Population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has been associated with greater morbidity and increased mortality in certain populations, such as those with chronic medical conditions, the elderly, and pregnant women. Our goal was to determine if COVID-19 infection during pregnancy increased the risk of preeclampsia in a population of women with increased risk factors for preeclampsia. We present a prospective observational matched case-control study of 100 deliveries with confirmed SARS-CoV2. Specifically, we investigated the maternal and neonatal outcomes in a high-risk population of pregnant women. Among women with COVID-19, the severity of symptoms was associated with the incidence of preeclampsia, but not with pre-existing diabetes or hypertension. Women with more severe symptoms were more likely to delivery pre-term with smaller babies. After adjusting for diabetes, hypertensive women with COVID-19 had an increased risk of preeclampsia aOR4.3 [1.5,12.4] compared to non-hypertensive women with COVID-19. After adjusting for hypertension, women with diabetes and COVID-19 had an increased risk of preeclampsia aOR3.9 [1.2,12.5]. This relationship was not seen among women without COVID-19. For women who had pre-existing diabetes or hypertension, the risk of developing preeclampsia was only increased if they were also diagnosed with COVID-19, suggesting that in our population of women the risk of preeclampsia is not associated with pre-existing diabetes or hypertension.

COVID‐19 Increases Markers of Endothelial Damage in Normotensive Pregnant Women

COVID‐19 (CV19) is a disease caused by SARS‐CoV‐2 and has caused a pandemic since discovered in 2019, resulting in over 5 million deaths worldwide. The impact of CV19 on pregnancy are still under investigation and are potentially long‐lasting. However studies have reported that pregnant women affected by CV19 have an increased risk of preterm delivery, pregnancy complications, organ failure, respiratory distress, increased inflammation, increased hospitalization and poor fetal outcomes compared to women who do not contract CV19 during pregnancy. Outside of the pregnant literature, data reports that comorbidities associated with CV19 are associated with inflammation and hypertension (i.e. endothelial damage, kidney damage). In the current study we investigated the relationship between endothelial damage and CV19, hypothesizing that women who contract CV19 during pregnancy will have an increase in endothelial damage and poor birth outcomes. Women were enrolled into an IRB approved study and whole blood was collected at the time of hospital admission for delivery. Pregnant women (n=7/group) were grouped into one of three categories: Normotensive with no history of CV19, early (eCV19) a positive CV19 test > 10 weeks prior to delivery or term (tCV19) a positive CV19 test < 10 weeks prior to delivery. After centrifugation, plasma and serum was frozen at ‐20ºC for future use. Endothelial cells (HUVECs) were exposed to 10% serum for 24 hours, followed by media collection after an additional 24hr serum‐free media exposure. Circulating ET‐1 was extracted from plasma samples and ET‐1, sVCAM and ICAM were assayed via ELISA from both circulating and media samples. Data are expressed as mean±SEM. Comparisons between groups were analyzed via ANOVA followed by post‐hoc analysis. P < 0.05 was considered statistically significant. Endothelin is increased plasma of eCV19 (7.08±0.31,p<0.0001) and tCV19 (6.82±0.25,p<0.0001) normotensive women when compared to normotensive women (0.94±0.22) without the CV19 virus. SVCAM is also increased in plasma of eCV19 (1338±69.37, p<0.0001) and tCV19 (1355±36.18, p<0.0001) when compared to normotensive women without CV19 (75.51±4.67). There is no significance across groups in ICAM measurement in plasma from these women p=0.9024. There is also an increase in endothelin 1 measured in HUVEC media in eCV19 normotensive women (10.10±4.04, p=0.0318) when compared to normotensive women without CV19 (2.05±0.64) and an increase in SVCAM in eCV19 (72.65±5.69, p=0.0008) and tCV19 (50.78±10.68, p=0.002) normotensive women when compared to non‐CV19 normotensive women (4.94±0.86). There was no significance in birth outcomes as Gestational Age at delivery (37.79‐38.92 weeks, p=0.72), baby weight (2880‐3534 grams, p=0.33), systolic blood pressure (118.7‐123.1 mmHg, p=0.43) across groups. Results above shows that despite all women being normotensive, CV19 causes an increase in endothelial dysfunction regardless of when a patient contracted the virus. These results suggests that CV19 causes vasculature damage as endothelial damage markers are increased in both normotensive women who contracted the virus early and late as opposed to normotensive women without the virus. Despite all women being normotensive;CV19 is shown to be causing a direct effect on vasculature causing increases in endothelial damage markers.