Molecular and Physiological Aspects of SARS-CoV-2 Infection in Women and Pregnancy

Abstract

Whilst scientific knowledge about SARS-CoV-2 and COVID-19 is rapidly increasing, much of the effects on pregnant women is still unknown. To accommodate pregnancy, the human endometrium must undergo a physiological transformation called decidualization. These changes encompass the remodeling of endometrial immune cells leading to immunotolerance of the semi-allogenic conceptus as well as defense against pathogens. The angiotensin converting enzyme 2 (ACE2) plays an important regulatory role in the renin-angiotensin-system (RAS) and has been shown to be protective against comorbidities known to worsen COVID-19 outcomes. Furthermore, ACE2 is also crucial for decidualization and thus for early gestation. An astounding gender difference has been found in COVID-19 with male patients presenting with more severe cases and higher mortality rates. This could be attributed to differences in sex chromosomes, hormone levels and behavior patterns. Despite profound changes in the female body during pregnancy, expectant mothers do not face worse outcomes compared with non-pregnant women. Whereas mother-to-child transmission through respiratory droplets during labor or in the postnatal period is known, another question of in utero transmission remains unanswered. Evidence of placental SARS-CoV-2 infection and expression of viral entry receptors at the maternal-fetal interface suggests the possibility of in utero transmission. SARS-CoV-2 can cause further harm through placental damage, maternal systemic inflammation, and hindered access to health care during the pandemic. More research on the effects of COVID-19 during early pregnancy as well as vaccination and treatment options for gravid patients is urgently needed.

Keywords: ACE2; COVID-19; SARS-CoV-2; decidualization; pregnancy; vertical transmission; women.

Figure 1

Menstrual cycle and decidualization. The human menstrual cycle repeats itself in 28-day intervals. The start is marked by the onset of menstruation. Subsequently, the endometrium enters the proliferative phase, during which it increases in thickness as a response to high estrogen levels (pink, dotted line). In the secretory phase, decidualization occurs with remodeling of spiral arteries, mesenchymal-epithelial transition of stromal cells and alterations in the endometrial immune system, e.g., increase in uterine natural killer cells. These changes are triggered and regulated by progesterone (green, dashed line) and mainly take place in the upper part of the endometrium, the stratum functionalis, which is also shed during menstruation. ACE2 expression is increased by decidualization in the secretory phase (red, solid line).

Figure 2

The renin-angiotensin-system and ACE2. Triggered by low blood pressure, low blood volume and low sodium levels as well as sympathetic activity, the kidney secretes renin. Renin, a protease, cleaves angiotensinogen, secreted by the liver, into angiotensin I. Angiotensin I is then converted by the angiotensin-converting enzyme, which can be found in membranes of endothelial cells most abundantly in the lungs and kidneys, into angiotensin II. Various effects are caused by angiotensin II, which ultimately result in an increase of blood pressure and volume. The angiotensin-converting enzyme 2 works as a counterbalance to ACE by cleaving angiotensin I and angiotensin II into Ang 1–9* and Ang 1–7, respectively. (*Ang1–9 is postulated to exert similar effects as Ang1–7, though current data is limited and needs further validation). Activation of this pathway leads to vasodilation, inhibits cell proliferation and has anti-inflammatory effects. During pregnancy, maternal and fetal tissues contribute to the production of ACE2, leading to systemic vasodilation.

Figure 3

Structure of SARS-CoV-2 and cell entry. The Severe Acute Respiratory Syndrome Coronavirus 2 is made up of four structural proteins (envelope, membrane, spike and nucleocapsid protein) and has a single-stranded positive-sense RNA. For SARS-CoV-2 to infect cells of the respiratory tract, the spike protein first has to be cleaved by the transmembrane protease serine 2 (TMPRSS2), before it can interact with the angiotensin-converting enzyme 2 (ACE2) receptor. The virus then enters the cell through endocytosis.

Figure 4

Infection during pregnancy. Several pathogens (viruses, bacteria and parasites) are known to be vertically transmitted during pregnancy. Possible consequences of infection during pregnancy include organ malformations, preterm birth and death of the fetus.