In a recent study posted to Research Square*, researchers evaluated pregnancy-specific responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Background

Mounting evidence suggests an increased risk of adverse coronavirus disease 2019 (COVID-19) outcomes in pregnant women. In addition, pregnant women with COVID-19 experience more obstetrical complications such as preterm birth, stillbirth, and preeclampsia.

Therefore, COVID-19 during pregnancy does not only adversely impact the mother but also the offspring. Hence, there is a pressing need to comprehensively explore the pregnancy-driven immune responses and biological processes underlying the susceptibility to the severe disease.

The study and findings

In the present study, researchers profiled the proteomes of non-pregnant and pregnant COVID-19 patients. Plasma samples were obtained from 101 pregnant individuals; 72 women were positive for SARS-CoV-2 at admission, and the remaining 29 served as controls. Body mass index (BMI), parity, maternal age, and the frequency of chronic hypertension were comparable between controls and infected women.

Six COVID-19 patients were asymptomatic, 20 had mild COVID-19, 13 had moderate disease, 12 were severe, and 21 were critically ill. Additionally, plasma samples were obtained from 93 non-pregnant individuals. Fifty-two were COVID-19 patients, and 41 were controls. Most COVID-19 cases in the non-pregnant cohort were critically ill (67%) or severe (23%).

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More than 7000 protein analytes were determined in COVID-19 cases and controls between non-pregnant and pregnant individuals using SOMAScan. When pregnant COVID-19 patients were compared to controls after adjusting for BMI, maternal age, and gestational age at sampling, the authors identified 68 differentially abundant proteins in asymptomatic cases, 81 in mild cases, 242 in moderate cases, 144 in severe cases, and 1072 in critically ill patients.

In the non-pregnant cohort, the team identified 21 differentially abundant proteins in moderate cases, 1961 in severe cases, and 2966 in critically ill patients. Overall, they found 708 proteins that were differentially abundant with COVID-19 in pregnant women and 2605 that were differentially abundant in non-pregnant patients.

Of these, 486 proteins were significantly affected by COVID-19 in patients from non-pregnant and pregnant cohorts. Moreover, the authors investigated the biological processes enriched among the differentially abundant proteins. There were fewer enriched biological processes in pregnant COVID-19 patients than in non-pregnant patients.

Processes related to immune responses and extracellular matrix were enriched in pregnant COVID-19 patients, while protein localization, transport, and peptide biosynthetic pathways were enriched in non-pregnant individuals. In a subsequent analysis, researchers evaluated whether (any) proteins were dysregulated with COVID-19 between non-pregnant and pregnant patients.

The team identified 33 proteins from this analysis, which included those involved in wound healing and angiogenesis. Proteins like angiotensinogen and vascular endothelial growth factor receptor 1 decreased with COVID-19 in pregnant women but increased in non-pregnant cases. In line with this, proteins that had pregnancy-specific regulation with COVID-19 were enriched for pathways related to angiogenesis, vasodilation, and inflammatory response regulation.

Further, the authors found that soluble tumor necrosis factor receptor II and von Willebrand factor were enriched with COVID-19 irrespective of pregnancy. Besides, neutrophil elastase was also elevated in non-pregnant and pregnant COVID-19 patients. Inflammatory cytokines such as interleukin (IL)-6, IL-18, and IL-1β were elevated in COVID-19 patients relative to controls in non-pregnant and pregnant cohorts.

IL-1α was downregulated only in pregnant COVID-19 patients. In contrast, interferon-γ was decreased in non-pregnant COVID-19 cases but not in pregnant patients. COVID-19 induced a cytokine storm regardless of pregnancy; however, the immune response was dampened in pregnant individuals.

Furthermore, the research team explored whether the proteomic profiles could distinguish between COVID-19 patients and controls. To this end, they generated random forest models, including up to 50 proteins, and assessed for accuracy through leave-one-out cross-validation. The resultant model accurately distinguished COVID-19 cases and controls.

Moreover, models were separately derived based on the disease severity, and the accuracy in differentiating severe cases from controls was higher than that for moderate cases and controls. Similar high accuracy was also evident for differentiating asymptomatic/mild cases from controls.

Conclusions

The present study observed that COVID-19 drives changes in the proteomes of non-pregnant and pregnant individuals. The authors found a dampened immune response to COVID-19 in pregnant patients compared to non-pregnant subjects, irrespective of disease severity. Pregnant patients mounted a tailored proteomic response to protect the conceptus from inflammation, while non-pregnant patients had a robust response.

Overall, the study represents a comprehensive characterization of proteomes of non-pregnant and pregnant COVID-19 patients. These findings underscore the distinct immune modulation in the non-pregnant and pregnant states. Further investigations are required to delineate the molecular mechanisms of SARS-CoV-2-induced maternal cytokine storm and its impact on the offspring.

*Important notice

Research Square 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.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.