key: cord-0897343-3wocr9ko
authors: Chen, Ruirong; Zhang, Shaofen; Su, Sheng; Ye, Haiyan; Shu, Haihua
title: Interactions Between Specific Immune Status of Pregnant Women and SARS-CoV-2 Infection
date: 2021-08-12
journal: Front Cell Infect Microbiol
DOI: 10.3389/fcimb.2021.721309
sha: 09cff66e299ff315a0f8f55edc065cae6faf22f6
doc_id: 897343
cord_uid: 3wocr9ko

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the Coronavirus Disease 2019 (COVID-19) global pandemic. Because it is a new and highly contagious coronavirus, most people, especially pregnant women, lack immunity. It is therefore important to understand the interaction between why pregnant women are susceptible to SARS-CoV-2 and the specific immune systems of pregnant women. Here, we provide an overview of the changes that occur in the immune system during pregnancy, the activation and response of the immune system in pregnant women with COVID-19, adverse pregnancy outcomes in pregnant women with COVID-19, and the treatment and prevention of COVID-19 in this population.

Coronavirus Disease 2019 is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has become a public health emergency of international concern in recent times. According to past epidemiological data, pregnant women are significantly more susceptible to influenza viruses and have higher morbidity from these infections than non-pregnant women . With further expansion of the pandemic, pregnant women have gradually been found to be susceptible to SARS-CoV-2, which is mainly related to the special immune states of women during pregnancy (Zhu et al., 2020) . Although pregnant women are at an increased risk for SARS-CoV-2 infection, the majority of pregnant women with COVID-19 have mild symptoms; about one-fifth of them develop moderate or severe disease (Andrikopoulou et al., 2020; Islam et al., 2020) . The results of a meta-analysis of pregnant women and showed that 51% of pregnant women infected with COVID-19 had fever (vs. 91% non-pregnant patients) and 31% had cough (vs. 67% non-pregnant patients) . On the other hand, studies have shown COVID-19 combined with pregnancy can lead to premature delivery, fetal distress, fetal vascular perfusion, premature rupture of membranes, and other adverse pregnancy events . Although the treatments for COVID-19 are evolving, health care providers do not have specific treatments for pregnant women. Understanding the changes that occur in the immune system during pregnancy and the interaction between the immune system and COVID-19 is extremely important, because each key link is expected to become a potential target of COVID-19, and provides new methods and ideas for the treatment of COVID-19 in pregnant women.

Compared to non-pregnant women, pregnant women have a unique state of immunity. This status can affect how pregnant women respond to viral infections (Silasi et al., 2015) , and SARS-CoV-2 is no exception. The main changes are summarized below ( Table 1) :

The CD3+/CD4+ and CD3+/CD8+ peripheral blood T lymphocyte and specific antiviral serum antibody counts were low in the pregnant patient (Chan et al., 2010) . In addition to a decrease in the number of T cells in the blood during pregnancy, these cells are significantly less active when stimulated (Vazquez et al., 2015) .

Transferring CD4+ T cell populations to T helper cell 2 (Th2) phenotypes during pregnancy (a response that promotes humoral rather than cellular immune responses) (Piccinni et al., 2000) , reduced T helper cell 1 (Th1) reactivity may lead to reduced clearance of infected cells, increasing susceptibility to COVID-19 (Veenstra Van Nieuwenhoven et al., 2003) . B cells are also affected by pregnancy, as their production is reduced during pregnancy (Medina et al., 1993) .

Circulating natural killer (NK) cells decrease during pregnancy (Veenstra Van Nieuwenhoven et al., 2003) . Since NK cells make up one fifth of the lymphocytes in the lung parenchyma, their role may provide a strong and extensive innate immune response to SARS-CoV-2 infection. Therefore, the decrease of NK cells is closely related to viral infection (Bozzano et al., 2021) ..

Dendritic cells (DCs) are antigen-presenting cells that play a critical role in antiviral immunity (Liu, 2005) . DCs are divided into two major types known as plasmacytoid cells (pDCs) and myeloid cells (mDCs) (Merad et al., 2013) . Most studies have shown that the proportion of mDC/pDC is higher in pregnant women than in non-pregnant women (Darmochwal-Kolarz et al., 2003; Shin et al., 2009) . During pregnancy, the production of interferon alpha (IFN-a) increases due to stimulation by toll-like receptors (TLRs), while the occurrence frequency of pDC decreases slightly, which may reduce the initiation of adaptive antiviral immune responses (Cordeau et al., 2012) .

The phagocytic function of neutrophils and monocytes was significantly reduced in pregnant compared to non-pregnant women (Lampéet al., 2015) .

The levels of interferon-g (IFN-g), vascular endothelial growth factor (VEGF), interleukin (IL)-1a, IL-1b, IL-6, IL-12, IL-17, IL-2, TNF-a (tumor necrosis factor a), and chemokines were decreased (Elenkov et al., 2001; Dashraath et al., 2020) . On the contrary, IL-4, IL-10, IL-13, and transforming growth factorb (TGF-b) levels were increased (Elenkov et al., 2001; Dashraath et al., 2020) . Their changes during pregnancy are associated with a reduction in symptoms found in patients with COVID-19 (Pazos et al., 2012; Dashraath et al., 2020) .

Circulating progesterone (P4) and steroid 17b-estradiol (E2) levels are elevated during pregnancy. The anti-inflammatory effects of E2 in innate immunity include inhibition of the production of pro-inflammatory cytokines such as IL-6 and IL-1b, tumor necrosis factor-a, monocytes, and macrophages which is a major factor in the COVID-19 cytokine storm and powerful inhibition of monocyte chemoattractant protein-1 (MCP-1), thereby preventing innate immune cells, especially neutrophils and monocytes, from migrating to inflammatory areas. E2 stimulates CD4+ T helper cells to produce anti-inflammatory cytokines such as interleukin-4 (IL-4) and IL-10. In general, high E2 concentrations favor helper T cell type 2 (Th2) antiinflammatory responses. E2 reduces production of interleukin-17 (IL-17) by pro-inflammatory T helper cell 17 (Th17 cells). E2 enhances the expansion of regulatory T cells (Treg), thereby promoting immune tolerance. E2 also stimulates the production of antibodies by B cells (Straub, 2007) . P4 facilitates the CD4+ Thelper cell response from Th1 toward Th2 and the production of anti-inflammatory IL-4 and IL-10 cytokines (Szekeres-Bartho et al., 1996; Szekeres-Bartho and Wegmann, 1996) .

Th immune status of pregnant women with COVID-19 is unique which makes it easier for the virus to invade, and the rate of SARS-CoV-2 infection is higher in pregnant women than non-pregnant women. However, after SARS-CoV-2 invades a pregnant woman, her immune system confers a certain protective effect, and the serious consequences caused by the virus are likely reduced (Wei et al., 2020) . Pregnant women hospitalized for COVID-19 are less likely to develop symptoms than non-pregnant women of similar age (Allotey et al., 2020) (Figure 1) .

The angiotensin-converting enzyme 2 (ACE2) is a key receptor for coronavirus invasion. Similar to the way other coronaviruses invade the body, studies have shown that SARS-CoV-2 uses the spike glycoprotein (S) proteins to bind to its receptors on target cells (Wan et al., 2020; Zhou et al., 2020) . ACE2 expression and activity are enhanced during pregnancy (Levy et al., 2008) . Compared with non-pregnant women, pregnant women showed a two-fold increase in ACE2 receptor expression in different organs including the placenta, kidneys, and uterus (Brosnihan et al., 2004) . This automatically makes pregnant women more susceptible to SARS-CoV-2 than non-pregnant women.

SARS-CoV-2 infects alveolar epithelial cells by recognizing the ACE2 receptor. Following cell invasion, the virus replicates in large quantities, which activates immune cells. Interestingly, ACE2 has a lung-protective effect (Ziegler et al., 2020) , and elevated ACE2 levels in pregnant women make their lungs more protective than those of non-pregnant women, possibly reducing lung inflammation. In addition, angiopoietin 1-7 (Ang 1-7) produced by ACE2 degradation of Ang II was higher in pregnant women than in non-pregnant women, and the antiinflammatory effect of phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways regulated by MAS receptors specifically bound to Ang 1-7 was TABLE 1 | "Physiological changes in pregnant women" and "Effects of SARS-CoV-2".

Effects of SARS-CoV-2 CD3+ T cell Constructs TCR/CD3 complex and stabilizes its structure Participates T-cell activation signal transduction (Mesner et al., 2020) Decreases in level and activity when stimulated Weakens cellular immunity, and SARS-CoV-2 is more likely to invade CD4+ T cell Participates in the TCR antigen recognition process of TH cells (Horkova et al., 2020) Decreases in level and activity when stimulated Differentiates to Th2 phenotype -The activity of Th 1 phenotype decreases Weakens cellular immunity, and SARS-CoV-2 is more likely to invade Weakens humoral immunity, and the secretion of antibodies is reduced CD8+ T cell Killing effect on some antigens such as viruses and tumor cells (Horkova et al., 2020) Decreases in level and activity when stimulated

Weakens the ability of CD8+ T cells to kill target cells, and SARS-CoV-2 is more likely to invade NK cell Identifies target cells, killing agents (Huntington et al., 2020) Decreases Weakens innate immune response to SARS-CoV-2 DC cell Initiates, regulates, and maintains the immune response Activates NK cell (Chen et al., 2016) mDC/pDC↑ pDC↓ Weakens the initiation of adaptive immune response to SARS-CoV-2 Reduced activation of NK cell weakens the innate immune response to SARS-CoV-2 Neutrophil Chemotaxis Phagocytosis -Bactericidal action (Grunwell et al., 2019; Jaillon et al., 2020) Reduces phagocytosis SARS-CoV-2 is more likely to invade Monocytes Phagocytosis Antigen presentation (Guilliams et al., 2018) Reduces phagocytosis SARS-CoV-2 is more likely to invade 

Stimulates and activates the proliferation of B and T cells (Watson et al., 1979; Wilson and Livingstone, 2008) Inhibits differentiation of the Th17 cells (Laurence et al., 2007) Decreases

Stimulates and activates the proliferation of B and T cells Stimulates CD4+ T cells to differentiate into the Th2 phenotype Against the action of INF-g-activated macrophages (Junttila, 2018; Franke et al., 2020) Increases Reduces inflammatory response and reduces symptoms after SARS-CoV-2 infection

Stimulates T-cell proliferation and CTL activation (Hirano, 2021) Decreases

IL-10 Inhibition of macrophage response Suppresses cellular immunity Promotes humoral immunity (Walter, 2014) Increases

Stimulates the proliferation of activated T cells, Promotes the differentiation of T0 cells to T1 cells Induces cytotoxic activity of CTL and NK cells 6 (Trinchieri, 2003; Furue et al., 2019) Decreases

Inhibits the release of IL-1, IL6, and other pro-inflammatory cytokines from monocytes Promotes the immune response of TH cells (Hart et al., 1999) Increases

Mediates tissue inflammation (Amatya et al., 2017) Decreases Reduces inflammatory response and reduces symptoms after SARS-CoV-2 infection Delays virus clearance and increases infection rate (Continued) also stronger than that in non-pregnant women (Passos-Silva et al., 2013) . This results in less severe COVID-19 symptoms in pregnant women than in non-pregnant women, fewer cytokine storms, and less progression towards acute respiratory distress syndrome (ARDS), multiple organ dysfunction, and death. The pattern recognition receptors (PRRs) expressed by lung epithelial cells, macrophages, and DCs bind to damage-associated molecular patterns (DAMPs) produced by virus-infected epithelial cells and pathogen-associated molecular patterns (PAMPs) of the virus itself, which then activate nuclear factor-k-gene binding (NF-kB) and several mitogen-activated protein kinases (MAPKs), triggering a cascade of inflammatory responses and the release of chemokines. Inflammation is less severe in pregnant women and cytokine storms are less likely to occur. This is mainly caused by the following mechanisms. A physiological shift in pregnant women to a TH2 environment conducive to the expression of antiinflammatory cytokines (IL-4 and IL-10). The levels of IFN-g, VEGF, IL-1a, IL-1b, IL-6, IL-12, IL-17, and chemokines were decreased in pregnant woman, so the cascade of inflammatory cytokines was weaker than that of non-pregnant women. DCs activated by SARS-CoV-2 release IFN and IL-7 to promote immune inflammatory response and they trigger a direct antiviral response and manipulate the activation of NK cells and CTL (Hassanzadeh-Kiabi et al., 2017; Jamilloux et al., 2020) . During pregnancy, the occurrence frequency of pDC decrease. Thus, DC-mediated inflammatory response was reduced in pregnant women. The phagocytic function of neutrophils and monocytes is significantly reduced during pregnancy and also releases fewer cytokines. NK cells help clear virus-infected cells through a variety of mechanisms including direct contact, cytokine or chemokine secretion, and indirect influence on lateral and downstream adaptive immune responses by affecting dendritic cells and T cells (Moretta, 2002; Mavilio et al., 2006; Vivier et al., 2011) . The decrease of NK cells in pregnant women results in a significantly reduced inflammatory response in the body. The anti-inflammatory effects of E2 and P4 also play a role in reducing inflammatory response. As a result, the expression of pro-inflammatory and anti-inflammatory cytokines was relatively low in pregnant women with COVID-19. In particular, macrophage chemokines, referred to as major components of the cytokine storm during COVID-19 (Jafarzadeh et al., 2020) , including macrophage inflammatory protein 1-alpha (MIP1a), CTACK, RANTES, eotaxin, growth-related oncogene alpha (GRO-a), and TNF were found at significantly low levels in pregnant patients. At the same time, basic fibroblast growth factor (FGF), leukemia inhibitory factor (LIF), granulocyte colony-stimulating factor (G-CSF), platelet-derived growth factor subunit B (PDGF-BB), and other growth factors were also significantly lower in COVID-19-positive pregnant women than pregnant women without COVID-19 (Chen G. et al., 2021) . CD4+ and CD8+ T cells not only eliminate the virus, but also stimulate hypermacrophage syndrome, eventually causing a cytokine storm in SARS-CoV-2 patients . The CD3+/CD4+ and CD3+/CD8+ peripheral blood T lymphocytes were low, which will reduce clearance of infected cells and the appearance of cytokine storm. Patients with COVID-19 show both a B cell immune response and a follicle-assisted T cell response (Thevarajan et al., 2020) . In addition to producing antibodies, activated B cells also secrete IL-1, IL-6, IL-8, TNF, lymphotoxin-a (LT-A), G-CSF, granulocytemacrophage colony-stimulating factor (GM-CSF), macrophagecolony stimulating factor (M-CSF), IL-7, and other cytokines that can aggravate the cytokine storm (Vazquez et al., 2015) . Production of B cell lymphocytes is reduced during pregnancy, which alleviate the occurrence of cytokine storm.

A reduced inflammatory response also leads to delayed clearance of the virus and increased infection rates. This can lead to adverse obstetric outcomes.

Adverse obstetric outcomes of COVID-19 include miscarriage, intrauterine growth restriction, premature rupture of membranes, Promotes angiotensin conversion Key receptors on cell surface that bind to SARS-CoV-2 (Levy et al., 2008; Jamilloux et al., 2020; Zhou et al., 2020) Expression and activity are increased

Chance of SARS-CoV-2 invasion increases Enhances the protective effect of ACE2 on the lung after SARS-CoV-2 infection Ang 1-7)

Relaxation of blood vessels -Suppresses inflammation (Patel et al., 2016) Increases -Reduces inflammatory response and reduces symptoms after SARS-CoV-2 infection SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th cell, T helper cell; NK cell, natural killer cell; DC cell, dendritic cell; pDC, plasmacytoid cell; mDC, myeloid cell; IFN-g, interferon gamma; VEGF, vascular endothelial growth factor; IL-1a, interleukin 1 alpha; IL-1b, interleukin 1 beta; IL-2, interleukin 2; IL-4, interleukin 4; IL-6, interleukin 6; IL-7, interleukin 7; IL-8,interleukin 8; IL-10, interleukin 10; IL-12, interleukin 12; IL-13, interleukin 13; IL-17, interleukin 17; TNF, tumor necrosis factor; TGF-b, transforming growth factor-beta; LT-A, lymphotoxin-A; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, macrophage-colony stimulating factor; ACE2, angiotensin-converting enzyme 2; Ang 1-7, angiotensin-(1-7).

intrauterine/fetal distress, preeclampsia, vertical transmission, and preterm delivery (Dashraath et al., 2020; Schwartz, 2020) (Table 2) . Endothelial cell dysfunction is the core mechanism that leads to preeclampsia in pregnant women (Burton et al., 2019) . Endothelial dysfunction after SARS-CoV-2 infection is the key to progression of COVID-19, so pregnant women infected with COVID-19 are at an increased risk of developing preeclampsia (Bonaventura et al., 2021) .

The delicate balance between Treg and Th17 cells mediates the mother's tolerance to the fetus (Aluvihare et al., 2004; Lee J. H. et al., 2011) . In patients with COVID-19, the level of Treg cells (CD3 +CD4+CD25+ CD127low+) decreases Qin et al., 2020) , the level of Th17 cells (CCR6+ Th17) increases, and the ratio of Treg/Th17 cells decreases (Wu and Yang, 2020) . Reduced Treg cell count and increased Th17 cell percentage are associated with pregnancy complications such as miscarriage, preeclampsia, and preterm delivery (Sasaki et al., 2007; Xiong et al., 2010; Fu et al., 2014; Kouckýet al., 2014; Eghbal-Fard et al., 2019) .

IFN-g, TNF, IL-6, and IL-8 levels were significantly increased in COVID-19 patients , causing pregnant FIGURE 1 | SARS-CoV-2 binds to ACE2 in the alveolar epithelial cells and invades these cells. Entry of SARS-CoV-2 into the body activates dendritic cells and macrophages, which secrete cytokines to activate NK cells. These NK cells kill the target cells infected by SARS-CoV-2. TLRs on dendritic cells and macrophages recognize viruses and secrete cytokines that mediate the inflammatory response. The CD4 TCR on the surface of Th0 cell membrane specifically binds to the antigen-peptide MHC II molecular complex on the surface of dendritic cells and macrophages, promoting the differentiation of Th0 cells into Th1, Th2, Treg, Th9, and Th17 cells, and the cytokines secreted by these cells promote the inflammatory response. Th1 cells secrete cytokines to activate CTL, and CD8 TCR on the surface of CTL recognizes and binds to MHC-I on the surface of cells infected with SARS-CoV-2 to kill target cells. Th2 cells secrete cytokines that assist the activation of B cells, which are activated into plasma cells that produce neutralizing antibodies to clear SARS-CoV-2. At the same time, B cells secrete cytokines to promote the killing activity of NK cells. The cytokines secreted by each immune cell in the immune response act on the immune cells themselves and promote their secretion of cytokines, forming a vicious cycle, finally resulting in a cytokine storm and aggravating the inflammatory response. In addition, Ang 1-7 produced by hydrolysis of ACE2 specifically binds to the PI3K/Akt and ERK signaling pathways regulated by MAS receptors on the cell surface, and plays an anti-inflammatory and cellular protective role. The increase of ACE2 levels in pregnant women makes invasion by SARS-CoV-2 easier; however, at the same time, the level of Ang 1-7 also increases, and the protective effect on the alveolar surface epithelial cells is stronger than that of non-pregnant women. During pregnancy, the immune system changes, and the cytokines secreted by dendritic cells and macrophages are reduced, and the activation of Th0 cells and NK cells is weakened, resulting in less cytokine. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NK cell, natural killer cell; TLR, Toll-like receptors; Th0 cell, T helper cell 0; Th1 cell, T helper cell 2; Th2 cell, T helper cell 2; Treg, regulatory cells; Th9 cell, T helper cell 9; Th17 cell, T helper cell 17; CTL, cytotoxic T lymphocyte; MHC-I, major histocompatibility complex-I; Ang-(1-7), angiotensin-(1-7); ACE2, angiotensin-converting enzyme 2; PI3K, phosphoinositide 3-kinase; ERK, extracellularsignal-regulated kinase;. Frontiers in Cellular and Infection Microbiology | www.frontiersin.org August 2021 | Volume 11 | Article 721309 women with COVID-19 to be more prone to miscarriage and premature rupture of membranes. The secretion of TNF-a, IL-8, and IL-6 by macrophages in the process of inflammation can lead to abortion, premature rupture of membranes, and preterm labor (Lee S. Y. et al., 2011; Roncari et al., 2013; Li et al., 2015; Li et al., 2020) . SARS-CoV-2 not only binds to ACE2 but also causes it to be downregulated, so Ang 1-7) also decreases (Glowacka et al., 2010) . Preeclampsia is associated with reduced plasma Ang 1-7) levels in the mother (Roncari et al., 2013) . COVID-19 increases the risk of preeclampsia in pregnant women.

Patients with COVID-19 have a higher incidence of thromboembolic complications (Knight et al., 2020) , and healthy pregnant women have higher levels of circulating clotting and fibrinolytic factors (such as fibrinolytic enzyme) (Di Renzo and Giardina, 2020) . Alterations in clotting and fibrinolysis are thought to play an important role in the pathogenesis of preeclampsia (Schjetlein et al., 1997) . Pregnant women with COVID-19 may have additive or co-operative risk factors for the onset of preeclampsia.

Studies have shown that that although vertical transmission of SARS-CoV-2 in utero is low, it is possible and appears to occur in a minority of pregnant women with COVID-19 in the third trimester (Fenizia et al., 2020; Kotlyar et al., 2021) .

There are several treatments that hold promise for preventing and treating pregnant women with COVID-19 (Table 3) .

Bamlanivimab and etesevimab are recombinant human immunoglobulin G1 antibodies, which is a therapy that has proven to be more effective. A randomized clinical trial showed the treatment to be effective . Phase III data on bamlanivimab plus etesevimab in COVID-19 patients showed that among non-hospitalized patients with mild-to-moderate COVID-19 disease, bamlanivimab plus etesevimab led to a lower incidence of COVID-19-related hospitalization and death than the placebo and accelerated the decline in the SARS-CoV-2 viral load (Dougan et al., 2021) . The study population included high-risk groups such as immunosuppressed states, chronic diseases, immunodeficiency, and obesity. All these patients benefited from the treatment. Although there is still no data showing that it is safe for pregnant women, we believe this is a very promising treatment.

Torzumab is an IL-6 receptor antagonist and a meta-analysis of torzumab use and COVID-19 inpatient mortality showed that torzumab reduced all-cause mortality in COVID-19 inpatients within 28 days (Shankar-Hari et al., 2021) . In addition, studies have shown that torzumab is effective in patients with severe (Virdis et al., 2011; Brenner et al., 2015) Increases Abortion Premature rupture of membranes IL-6

Stimulates the synthesis of APP in liver cells Stimulates the proliferation of activated B cells and secrete antibodies Stimulates T cell proliferation and CTL activation (Hirano, 2021) Increases Abortion Premature rupture of membranes IL-8

Chemotactic neutrophils (Li Jeon et al., 2002) Increases Abortion Premature rupture of membranes ACE2

Promotes angiotensin conversion -Key cell surface receptor that binds to SARS-CoV-2 (Levy et al., 2008; Jamilloux et al., 2020; Zhou et al., 2020) Decreases Preeclampsia

Ang-(1-7) -Relaxation of blood vessels -Suppresses inflammation 10 (Patel et al., 2016) Decreases Preeclampsia

Blood coagulation factor -Participates in blood clotting (Langarizadeh et al., 2021) Increases Thromboembolism ECs, endothelial cells; Treg cells, regulatory cells; Th 17 cells, T helper cell 17; IFN-g, interferon gamma; TNF, tumor necrosis factor; IL-6, interleukin 6; IL-8, interleukin 8; ACE2, angiotensinconverting enzyme 2; Ang 1-7), angiotensin-(1-7).

COVID-19 during pregnancy and is a treatment option for COVID-19 during pregnancy (Naqvi et al., 2020) .

There is some evidence that IFN can show anti-SARS-CoV-2 effect (Busnadiego et al., 2020; Monk et al., 2021) , especially as inhaled nebulized interferon beta-1a (SNG001). Studies have shown that none of the patients who received IFN during pregnancy experienced stillbirth or delivered babies with severe malformations, and IFN did not significantly increase the risk of malformation, miscarriage, stillbirth, or preterm birth. Therefore, IFN is likely effective and safe in terms of COVID-19 during pregnancy (Yazdani Brojeni et al., 2012) .

Remdesivir, a novel broad-spectrum antiviral nucleotide prodrug, has been shown to inhibit the replication of SARS coronavirus in vitro. Published results have suggested that the use of remdesivir may reduce clinical recovery time in patients with COVID-19 (Beigel et al., 2020) . The manufacturer safety data of remdesivir indicate no reproductive developmental toxicity in animals at clinically relevant doses; furthermore, embryonic toxicity was only noted when systemically toxic doses were administered to female animals before conception (Maldarelli et al., 2020) . Studies of the use of remdesivir did not document specific adverse outcomes in pregnant women (Mulangu et al., 2019; Burwick et al., 2020) . These data provide patients and clinicians with reliable information about the safety of remdesivir in the treatment of pregnant women with COVID-19. Remdesivir is expected to be beneficial for COVID-19 therapy.

Dexamethasone is a common anti-inflammatory drug. It is known that glucocorticoids inhibit inflammation through nongenetic mechanisms, such as binding to glucocorticoid receptors on the T-cell membrane, resulting in disorder of receptor signals and immune response, and interaction with calcium and sodium across the cell membrane, leading to rapid resolution of inflammation (Langarizadeh et al., 2021) . Hence, it may play a vital role in the treatment of COVID-19. The administration of prenatal corticosteroids to women at risk of preterm birth has been shown to have significant benefits in neonatal morbidity and mortality (Kemp et al., 2016) , which make it reasonable for COVID-19 patients to use dexamethasone during pregnancy.

There is evidence for pregnant women with COVID-19 that appropriate use of magnesium sulfate, aspirin, metformin, and anticoagulants can help cure the disease and reduce adverse outcomes such as preeclampsia, premature birth, and miscarriage D'Souza et al., 2021) .

Vitamin D is an immunomodulatory hormone that has been established to be effective against a variety of upper respiratory tract infections. Vitamin D prevents excessive inflammatory response and accelerates the healing process in affected areas, primarily in lung tissue (Mohan et al., 2020) . Moreover, Treg/ Th17 imbalance can be corrected with vitamin D supplementation in vivo (Ji et al., 2019) . The imbalance of Treg/Th17 in COVID-19 patients not only leads to uncontrolled cytokine release and increased inflammatory response in COVID-19 patients but also leads to adverse obstetric outcomes in pregnant patients. Vitamin D therefore holds promise as a complementary treatment.

High-dose inhaled nitric oxide (160-200 ppm) has shown antimicrobial effects against bacteria and viruses (including SARS-CoV), and is used as an adjunct treatment for ARDS and pulmonary hypertension. A case series of pregnant patients with severe COVID-19 treated with high-dose nitric oxide demonstrated improvement in hypoxemia and tachypnea with no adverse neonatal effects (Safaee Fakhr et al., 2020) . Hence, it also holds promise as a complementary treatment.

We wish to highlight the need for close interdepartmental collaboration in caring for pregnant women presenting with COVID-19.

For the influenza virus, studies have shown significant reductions in low birth weight and preterm birth in vaccinated women compared to unvaccinated women (Heath et al., 2020) , while other studies have not shown any association between vaccination and spontaneous abortion, preterm birth, birth defects, or small gestational age babies. Vaccination is one of the most promising preventive measures against COVID-19. Because pregnant women are more susceptible to SARS-CoV-2, vaccination during pregnancy is the most optimal strategy for preventing maternal and neonatal disease (Andreani et al., 2020; Heath et al., 2020) . A preliminary finding of mRNA safety of COVID-19 vaccine in pregnant women showed that vaccination is safe in the third trimester of pregnancy (Shimabukuro et al., 2021) . In addition to vaccination protecting women against COVID-19 and its complications during pregnancy, emerging evidence has shown transplacental transfer of SARS-CoV-2 antibodies after maternal COVID-19 vaccination during the third trimester, which suggests that maternal vaccination might provide some level of protection to the neonate (Gill and Jones, 2021; Gray et al., 2021; Rottenstreich et al., 2021) . To date, there is still little information on the efficacy and safety of vaccinating pregnant women. More extensive research is required regarding vaccinating pregnant women. Studies (Cheng et al., 2021) have shown that wearing a surgical mask can be a very cost-effective method to prevent the spread of virus. Because the vaccine does not provide 100% protection against COVID-19, mask-wearing is especially important for pregnant women who are more vulnerable to infection.

COVID-19-related immune system changes in pregnant women involve multiple cytokines, cells, and receptors. The unique immune status of pregnant women makes them more susceptible to SARS-CoV-2 invasion. However, after SARS-CoV-2 invades a pregnant woman, the immune system of the body has a certain protective effect, which reduces the serious consequences caused by the virus. However, changes in the immune system caused by the virus can also lead to poor pregnancy outcomes. Therefore, it is of great significance to accurately identify COVID-19 inflammatory pathways and therapeutic targets in pregnant women. The efficacy of the current COVID-19 treatment for pregnant women is still not satisfactory. Many clinical studies of drugs and vaccines have excluded pregnant women. The treatment of pregnant women has become a challenging problem, and more studies are needed to address these issues.

HS and HY conceived and designed the study. RC, SZ, and SS performed the literature search and drafted the manuscript. All authors contributed to the article and approved the submitted version. 

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COVID-19 Vaccine Response in Pregnant and Lactating Women: A Cohort Study

Children With Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance

Developmental and Functional Heterogeneity of Monocytes

Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice

Differential Responses of Human Monocytes and Macrophages to IL-4 and IL-13

Autocrine Type I IFN Signaling in Dendritic Cells Stimulated With Fungal b-Glucans or Lipopolysaccharide Promotes CD8 T Cell Activation

Inclusion of Pregnant Women in COVID-19 Vaccine Development

IL-6 in Inflammation

Vascular Endothelial Growth Factor Receptor-2: Structure, Function, Intracellular Signalling and Therapeutic Inhibition

Dynamics of the Coreceptor-LCK Interactions During T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells

Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China

The Cancer-Natural Killer Cell Immunity Cycle

Clinical Characteristics and Neonatal Outcomes of Pregnant Patients With COVID-19: A Systematic Review

Contribution of Monocytes and Macrophages to the Local Tissue Inflammation and Cytokine Storm in COVID-19: Lessons From SARS and MERS, and Potential Therapeutic Interventions

Neutrophil Diversity and Plasticity in Tumour Progression and Therapy

Should We Stimulate or Suppress Immune Responses in COVID-19? Cytokine and Anti-Cytokine Interventions

The Role and Mechanism of Vitamin D-Mediated Regulation of Treg/Th17 Balance in Recurrent Pregnancy Loss

Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes

The Clinical Use of Corticosteroids in Pregnancy

IL-6: Regulator of Treg/Th17 Balance

Characteristics and Outcomes of Pregnant Women Admitted to Hospital With Confirmed SARS-CoV-2 Infection in UK: National Population Based Cohort Study

Vertical Transmission of Coronavirus Disease 2019: A Systematic Review and Meta-Analysis

Low Levels of Circulating T-Regulatory Lymphocytes and Short Cervical Length are Associated With Preterm Labor

Remdesivir: First Approval

Phagocytic Index of Neutrophil Granulocytes and Monocytes in Healthy and Preeclamptic Pregnancy

Ameri A. A Review on Function and Side Effects of Systemic Corticosteroids Used in High-Grade COVID-19 to Prevent Cytokine Storms

Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation

IL-6 Trans-Signaling System in Intra-Amniotic Inflammation, Preterm Birth, and Preterm Premature Rupture of the Membranes

Progesterone Promotes Differentiation of Human Cord Blood Fetal T Cells Into T Regulatory Cells But Suppresses Their Differentiation Into Th17 Cells

ACE2 Expression and Activity are Enhanced During Pregnancy

Neutrophil Chemotaxis in Linear and Complex Gradients of Interleukin-8 Formed in a Microfabricated Device

Inositol 1,4,5-Trisphosphate Receptors in Endothelial Cells Play an Essential Role in Vasodilation and Blood Pressure Regulation

IFN-g Modulates Ly-49 Receptors on NK Cells in IFN-g-Induced Pregnancy Failure

IPC: Professional Type 1 Interferon-Producing Cells and Plasmacytoid Dendritic Cell Precursors

Upregulation of TNF-a and IL-6 Induces Preterm Premature Rupture of Membranes by Activation of ADAMTS-9 in Embryonic Membrane Cells

Remdesivir Treatment for Severe COVID-19 in Third-Trimester Pregnancy: Case Report and Management Discussion

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

Characterization of the Defective Interaction Between a Subset of Natural Killer Cells and Dendritic Cells in HIV-1 Infection

Suppression of B Lymphopoiesis During Normal Pregnancy

The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting

Abnormal Pulmonary Endothelial Cells may Underlie the Enigmatic Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension

Loss of Nef-Mediated CD3 Down-Regulation in the HIV-1 Lineage Increases Viral Infectivity and Spread

Exploring Links Between Vitamin D Deficiency and COVID-19

Safety and Efficacy of Inhaled Nebulised Interferon Beta-1a (SNG001) for Treatment of SARS-CoV-2 Infection: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial

Natural Killer Cells and Dendritic Cells: Rendezvous in Abused Tissues

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

Tocilizumab and Remdesivir in a Pregnant Patient With Coronavirus Disease 2019 (COVID-19)

Angiotensin-(1-7): Beyond the Cardio-Renal Actions

Role of the ACE2/ Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure

The Influence of Pregnancy on Systemic Immunity

Role of Hormone-Controlled T-Cell Cytokines in the Maintenance of Pregnancy

Dysregulation of Immune Response in Patients With Coronavirus

Inflammation or Infection at the Time of Second Trimester Induced Abortion

Efficient Maternofetal Transplacental Transfer of Anti-SARS-CoV-2 Spike Antibodies After Antenatal SARS-CoV-2 BNT162b2 mRNA Vaccination

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19)

Proportion of Peripheral Blood and Decidual CD4(+) CD25(bright) Regulatory T Cells in Pre-Eclampsia

Markers of Intravascular Coagulation and Fibrinolysis in Preeclampsia: Association With Intrauterine Growth Retardation

An Analysis of 38 Pregnant Women With COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-Analysis

Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons

Differences in Circulating Dendritic Cell Subtypes in Pregnant Women, Cord Blood and Healthy Adult Women

Viral Infections During Pregnancy

The Complex Role of Estrogens in Inflammation

The Immunological Pregnancy Protective Effect of Progesterone is Manifested via Controlling Cytokine Production

Breadth of Concomitant Immune Responses Prior to Patient Recovery: A Case Report of non-Severe COVID-19

TGF-b Activation and Function in Immunity

Interleukin-12 and the Regulation of Innate Resistance and Adaptive Immunity

B Cells Responses and Cytokine Production are Regulated by Their Immune Microenvironment

The Immunology of Successful Pregnancy

Vascular Generation of Tumor Necrosis Factor-a Reduces Nitric Oxide Availability in Small Arteries From Visceral Fat of Obese Patients

Innate or Adaptive Immunity? The Example of

The Molecular Basis of IL-10 Function: From Receptor Structure to the Onset of Signaling

The Laboratory Tests and Host Immunity of COVID-19 Patients With Different Severity of Illness

Receptor Recognition by the Novel Coronavirus From Wuhan: An Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Molecular and Quantitative Analysis of Helper T Cell-Replacing Factors on the Induction of Antigen-Sensitive B and T Lymphocytes

Clinical Characteristics and Outcomes of Childbearing-Age Women With COVID-19 in Wuhan: Retrospective, Single-Center Study

Cutting Edge: CD4+ T Cell-Derived IL-2 is Essential for Help-Dependent Primary CD8+ T Cell Responses

TH17 Responses in Cytokine Storm of COVID-19: An Emerging Target of JAK2 Inhibitor Fedratinib

Proportional Changes of CD4 +CD25+Foxp3+ Regulatory T Cells in Maternal Peripheral Blood During Pregnancy and Labor at Term and Preterm

Potential Role of IFN-a in COVID-19 Patients and its Underlying Treatment Options

A Systematic Review of the Fetal Safety of Interferon Alpha

The Altered PD-1/ PD-L1 Pathway Delivers the 'One-Two Punch' Effects to Promote the Treg/ Th17 Imbalance in Pre-Eclampsia

Analysis of the Susceptibility to COVID-19 in Pregnancy and Recommendations on Potential Drug Screening

A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin

Clinical Analysis of 10 Neonates Born to Mothers With 2019-Ncov Pneumonia

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets Across Tissues

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.