This review evaluates whether pregnancy is a risk factor for COVID-19 by looking at the expression of immune markers such as immune cells and cytokines in order to have a better understanding on the pathophysiology of the disease, thus reducing maternal deaths. Pregnant women are more at risk of contracting COVID-19 due to their weakened immune system. Studies demonstrate that COVID-19 is an immune condition which is marked by reduced lymphocytes and elevated selected proinflammatory cytokines. Similar immune expression has been demonstrated in pregnancy by several studies. In addition, the placenta has been shown to possess ACE2 receptors on the villous cytotrophoblast and the syncytiotrophoblast and findings suggest that the coronavirus enters the host cells via these ACE2 receptors. The immune response in pregnancy increases the risk of contracting COVID-19. Both normal pregnancy and COVID-19 are marked by decreased lymphocytes, NKG2A inhibitory receptors, and increased ACE2, IL-8, IL-10, and IP-10 it therefore safer to conclude that pregnancy is a risk factor for COVID-19 development. Furthermore, the presence of the ACE2 receptors in the placenta may increase the risk of mother to baby transmission of the virus. Therefore, more studies investigating the link between pregnancy and COVID-19 are needed.
Immune expression in COVID-19 versus normal pregnancy
Coronavirus adaptive immune response
Following investigation in 99 Wuhan patients revealed, increased total neutrophils (38 %), reduced total lymphocytes (35 %), increased serum IL-6 (52 %) and increased c-reactive protein (84 %). Another Wuhan study reported that in 41 patients, there was increased total neutrophils, and decreased total lymphocytes in patients of ICU vs. non-ICU care. They further concluded that increased neutrophils and decreased lymphocytes also correlate with disease severity and death. Similar findings were reported by Chuan et al., (2019) who observed that patients with severe cases of COVID-19 tend to have lower lymphocyte counts, higher leukocyte counts and neutrophil-lymphocyte ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. More interestingly another study reported that most COVID-19 cases showed that lymphocytes were reduced to lower than 5% within 2 weeks after disease onset in COVID-19 patients. This clearly indicates that lymphocytes play a detrimental role in the progression of the diseases. A study conducted by Evangelos et al. investigating immune responses of 54 COVID-19 patients, 28 of whom had severe respiratory failure (SRF) indicated that; all patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Lymphocytes are a subtype of white blood cells that play a fundamental role in in protecting the immune system against infectious microorganisms and other foreign substances. These cells include natural killer cells (NK) cells, T cells (for cell mediated-cytotoxic adaptive) and B cells (for humoral, antibody driven adaptive immunity). Both NK and T cells are important for control of infection. In COVID-19 cases, depletion of these cells has been associated with the severity of the disease. Zheng et al. showed that the total number of NK and CD8+ T cells was decreased markedly in patients with COVID-19 and patients with SARS-CoV-2 infection. They also noticed an increase in the expression of NKG2A. NKG2A is an inhibitory receptor for NK cells. Increased NKG2A inhibits NK cells from performing their normal function.
Coronavirus innate immune response
Pro-inflammatory cytokines such as IL-1β, IL-6, IFNγ, MCP1 and IP-10 have been reported to be elevated into the blood of patients infected by SARS-CoV and MERS-CoV, which are both related to COVID-19 (Table 1). It was observed that patients with severe COVID-19, requiring intensive care in hospitals, exhibited higher blood plasma levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), GMCSF, IFNγ, IP10, MCP1, MIP1α, MIP1β, PDGFB, TNFα, VEGFA, IL2, IL7, IL10, GCSF, IP10, MCP1, cIP-10, MCP-1, MIP-1A, macrophage inflammatory protein 1α (MIP1α) and tumour necrosis factor (TNF). IL-6 levels in these patients continue to increase over time and are relatively more elevated in non-survivors than survivors. Also, patients with severe disease show a significantly higher percentage of CD14+CD16+ inflammatory monocytes in peripheral blood than patients with mild disease. These cells secrete inflammatory cytokines that contribute to the cytokine storm, including MCP1, IP-10 and MIP1α. cytokine storm also has ripple effects across the body. Elevated levels of cytokines such as TNF can cause septic shock and multi-organ failure which may result in myocardial damage and circulatory failure observed in some patients
Normal pregnancy immune response
The role of NK cells is to protect the body from diseases by secreting cytokines such as IFNγ and TNFα, which act on other immune cells like Macrophage to fight the infection. Natural Killer cells have also been shown to be involved in pregnancy. In a normal healthy pregnancy, the percentages of NK cells in the peripheral blood tend to increase during the first trimester, decrease in the second trimester, and decrease again in the third trimester. In addition, uterine NK cells during the first trimester become progressively less granular and decrease in number, leaving very few uNK cells at term. In both humans and mice, uNK cells participate in spiral artery remodeling with trophoblast cells. A study by Hanna et al., (2006) demonstrated that uNK cells have a limited ability to kill trophoblast cells, and instead they regulate trophoblast invasion by producing the chemokines interleukin (IL)-8 and IFN-inducible protein (IP)-10. In addition, uNK cells induce vascular growth by secreting angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Both VEGF and PIGF are known to play an important role in maintaining normal pregnancy development. However, exaggerated activation of uNK cells has been associated with pregnancy complications such as spontaneous abortion and pre-eclampsia (PE). During normal pregnancy NK cells are controlled by NK cells inhibitory receptors such as NKG2A. Activation of NK2GA receptors prevent NK cells from destroying trophoblast cells. Several studies have associated increased NKG2A expression with normal pregnancy development.Pregnancy has been described as an anti-inflammatory state since inflammation would result in maternal, and fetal complications. However, this may not entirely be accurate as some studies state otherwise. It has been reported that the first trimester is pro-inflammatory and the second is anti-inflammatory, and the third trimester shifts back into a pro-inflammatory phase. During the first trimester when implantation and placentation take place, an inflammatory response is triggered for the blastocyst to successfully penetrate the uterus for implantation and for trophoblast invasion to occur. At this stage the maternal system weakens, and the mother suffers from morning sickness, fatigue and headaches, indicating a pro-inflammatory phase. Moreover, in the second trimester, an anti-inflammatory state kicks in, and the fetus develops and growths swiftly. Maternal health also improves and morning sickness and other symptoms gradually disappear.
In the third trimester, the development of the fetus is complete and the delivery process begins in the maternal system. The immune response is activated again for the delivery of the baby and the placenta. For this to occur, the immune cells invade the myometrium thus creating a pro-inflammatory phase that activates contractions in the uterus. The latter is an indication that the shift in cytokines during pregnancy can trigger susceptibility to infectious diseases. In African countries where malaria is a burden to health, pregnant women are more at risk of contracting the disease in their first trimester, which is a pro-inflammatory phase, while other women in regions where there are cases of Lassa fever developed the disease mostly in their third trimester.
Coronavirus is a pro-inflammatory disease and therefore may easily invade suitable conditions. For instance, during the first and third trimester of pregnancy women are in a pro-inflammatory phase which is a suitable environment for the virus and are therefore at a higher risk of contracting the disease than the second trimester. However, there are currently no reports on mother to baby transmission of the coronavirus, which may be highly unlikely since the placenta creates a protective mechanism against viruses. The placenta has been reported to actively create protection against foreign pathogens by anti-microbial action as early as the first trimester of pregnancy. The trophoblast cells stimulate the expression of secretory leukocyte protease inhibitor (SLPI) and INF-β, which are known for their inhibitory action against viruses such as HIV. This mechanism protects the fetus against viral infections but not necessarily the mother. Therefore, the sensitisation of the placenta to induce an immune response creates vulnerability to infections in pregnant women. The binding site for the coronavirus is reported as the ACE2 receptor.
ACE2 receptor in pregnancy
The potent role of the renin angiotensin system (RAS) in pregnancy has been documented. The ACE2 receptor is critical for RAS since it is involved in the conversion of angiotensinogen into angiotensin 1, angiotensin 1 into angiotensin II, and angiotensin II into angiotensin (1–7). The expression of the ACE2 receptor has been reported in the placenta. Other members of the coronavirus family such as MERS-CoV and SARS-CoV have been involved in pregnancy complications. These viruses possess analogous pathogenic traits as the current SARS-CoV2. This may indicate that SARS-CoV2 is a potential threat to maternal and fetal health.
The expression of ACE2 in the placenta was reported to be higher in the villous cytotrophoblast, syncytiotrophoblast cells and in the decidua during the first trimester of pregnancy. The syncytiotrophoblast cells are involved in maternal and fetal gas exchange as well as nutrient supply. Since ACE2 is highly expressed in this region of the placenta, this not only increases the risk of the mother contracting SARS-Cov2, but is also plausible that transmission from mother to child may occur.
Conclusion
Evidence from the literature clearly indicates that healthy pregnant women are more susceptible to developing COVID-19 due to their immune response that predisposes them to develop COVID-19. Both normal pregnancy and COVID-19 are marked by decreased lymphocytes, NKG2A inhibitory receptors, and increased ACE2, IL-8, IL-10, and IP-10 it therefore safer to conclude that pregnancy is a risk factor for COVID-19 development.
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