COVID-19 Infection and Fetal-neonatal Outcomes

Coronaviruses are a large family of viruses known to cause illnesses ranging from the common cold to more serious illnesses such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). They are positive-stranded RNA viruses, with a corona-like appearance under the electron microscope, whose primary target cells are the epithelial cells of the respiratory and gastrointestinal tract. The 2019/20 COVID-19 respiratory disease pandemic, caused by a coronavirus, began in December 2019 in the city of Wuhan, the capital of the Chinese province of Hubei, which has subsequently spread to several countries around the world. In early January 2020, health authorities identified the virus responsible for the epidemic, designating it, initially as "Coronavirus 2019-nCoV" but later with the official name of "SARS-CoV-2". To date, seven Coronaviruses have been shown to be capable of infecting humans: Common Human Coronaviruses: HCoV-OC43 and HCoV-HKU1 (Betacoronavirus) and HCoV-229E and HCoV-NL63 (Alphacoronavirus); they can cause common colds but also severe lower respiratory tract infections; other human coronaviruses (Betacoronaviruses): SARS-CoV, MERS-CoV and 2019-nCoV (now referred to as SARS-CoV-2).

SARS-CoV-2 is therefore the seventh virus of the same family that involves humans, spreads through respiratory droplets and direct contact. The most common symptoms of the disease include fever, cough, asthenia or myalgia, wheezing and headache, and the most serious complication is acute respiratory distress syndrome (ARDS). The new coronavirus has continued to spread to multiple countries and continents so much so that the outbreak was declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO) on January 30, 2020.

In the first phase of world emergency, characterized by high morbidity and mortality, scientific interest has been mainly focused on the study of the transmission mechanisms of the infection, diagnostic tools and therapies for ARDS, especially in elderly patients and with co-morbidities. Interest has rapidly spread to other categories of patients and in particular to pregnancy, on which the virus could impact in different ways, with consequences for both the mother and the fetus.

During pregnancy, different changes in the immune system and adaptive changes affecting organs and systems are observed in relation to the gestational period, among which those affecting the respiratory system are highlighted, particularly evident in the third trimester including, upper airway mucosal edema induced by elevated levels of estrogen and progesterone, elevation of the diaphragm and consequent limited lung expansion, and high oxygen consumption, all conditions that increase the susceptibility of pregnant women to respiratory insults.

The maternal immune system during pregnancy undergoes specific adaptations aimed at establishing and maintaining a fetal allogeneic tolerance while preserving the ability to protect against external infectious agents. It goes from a pro-inflammatory state in the first trimester (important for implantation and placentation) to an anti-inflammatory state in the second trimester (necessary for fetal growth), and finally returns to a pro-inflammatory state again in the third trimester and during childbirth. In addition, innate immunity cells, that is, NK cells and monocytes respond more actively to viral insults, while the adaptive immune response is down-regulated (Hong Liu et al). As for CD4 + (Th) T cells, involved in the regulation of the inflammatory response through the production of cytokines, there is a shift in the maternal immune response from Th1 (with pro-inflammatory action) towards Th2 (with anti-inflammatory action ), a crucial modification for maintaining maternal-fetal tolerance (Wegmannetal et al.).

In the first phase of world emergency, characterized by high morbidity and mortality, scientific interest has been mainly focused on the study of the transmission mechanisms of the infection, diagnostic tools and therapies for ARDS, especially in elderly patients and with co-morbidities. Interest has rapidly spread to other categories of patients and in particular to pregnancy, on which the virus could impact in different ways, with consequences for both the mother and the fetus.

During pregnancy, different changes in the immune system and adaptive changes affecting organs and systems are observed in relation to the gestational period, among which those affecting the respiratory system are highlighted, particularly evident in the third trimester including, upper airway mucosal edema induced by elevated levels of estrogen and progesterone, elevation of the diaphragm and consequent limited lung expansion, and high oxygen consumption, all conditions that increase the susceptibility of pregnant women to respiratory insults.

It is widely demonstrated that maternal systemic infections, which cause instability in the delicate balance of the immune system, may be related to the onset of complications during pregnancy, such as increased risk of miscarriage, intrauterine growth retardation, death fetal intrauterine.

Based on these pathophysiological assumptions, it is conceivable that SARS-CoV-2 infection could clinically modify the course of pregnancy and lead to fetal-neonatal complications.

Recent studies in the literature have shown that severe forms of COVID-19 disease are associated with a cytokine storm, characterized by increased concentrations of IL-2, IL-7, IL-10, G-CSF (granulocyte-colony stimulating factor), interferon-γ-inducible protein, MCP (monocyte chemoattractant protein), MIP- α (macrophage inflammatory protein alpha) and TNF α (tumor necrosis factor α). It has been hypothesized that during pregnancy this cytokine cascade could induce an even more severe inflammatory state, particularly in the first and third trimester of pregnancy (Hong Liu et al).

Recently, Ashary et al. analyzed the possible presence of the virus at the level of the syncytiotrophoblast, noting that in 12% of patients with active COVID-19 infection, the virus was identifiable at the placental level. Furthermore, the target receptors of the virus for entry into the cell, ACE-2 and TMPRSS2, are significantly expressed and used by the virus also at the placental level, so SARS-CoV-2 could potentially, interacting with these targets, alter the syncytiotrophoblastic unit and, consequently, the placental function (Seethy et al.)

Although the current evidence does not support a vertical intrauterine transmission of coronaviruses (Chen et al), it is likely that it is the same maternal infection and the inflammatory state in the course of the disease that can negatively influence the maternal-fetal outcome.

Given the multiple characteristics common to SARS-CoV1, MERS and SARS-CoV2 infections, of particular relevance were the studies conducted by Wong et al on SARS-CoV-1 infection in the first trimester, in which four out of seven women ( 57%), who contracted SARS during the first trimester, then had a miscarriage, and that of Alfaraj et al on MERS infection, in which there was a single case of a woman with MERS in the first trimester, who never developed symptoms of the disease, and carried the pregnancy to term.

A recent systematic review that included all published reports on Coronaviruses (COVID-19, SARS, and MERS) in pregnancy showed that preterm delivery is the most frequently reported adverse event in these women, and that COVID-19 is associated with an increased risk of preeclampsia and caesarean section. Nevertheless, the limited sample size, the main inclusion of cases reported for acute respiratory symptoms, the absence of information on previous pathologies potentially capable of complicating pregnancy, do not allow to extrapolate strong evidence on the course of infection in pregnancy ( Di Mascio et al. 2020).

Recently, Ashary et al. analyzed the possible presence of the virus at the level of the syncytiotrophoblast, noting that in 12% of patients with active COVID-19 infection, the virus was identifiable at the placental level. Furthermore, the target receptors of the virus for entry into the cell, ACE-2 and TMPRSS2, are significantly expressed and used by the virus also at the placental level, so SARS-CoV-2 could potentially, interacting with these targets, alter the syncytiotrophoblastic unit and, consequently, the placental function (Seethy et al.)

Although the current evidence does not support a vertical intrauterine transmission of coronaviruses (Chen et al), it is likely that it is the same maternal infection and the inflammatory state in the course of the disease that can negatively influence the maternal-fetal outcome.

Given the multiple characteristics common to SARS-CoV1, MERS and SARS-CoV2 infections, of particular relevance were the studies conducted by Wong et al on SARS-CoV-1 infection in the first trimester, in which four out of seven women ( 57%), who contracted SARS during the first trimester, then had a miscarriage, and that of Alfaraj et al on MERS infection, in which there was a single case of a woman with MERS in the first trimester, who never developed symptoms of the disease, and carried the pregnancy to term.

At the moment there are no data in the literature on the impact of SARS-CoV-2 infection on early pregnancy as the data currently available in the literature concern women hospitalized in serious clinical conditions during the first wave of the March 2020 pandemic (Di Mascio et al.). Conversely, other studies report low seroconversion rates for the virus. Therefore, the current status of the scientific literature does not allow for general and wide-ranging implications (La Cour Freiesleben et al.).

Furthermore, easier access to tests for the identification of COVID-19 and the introduction by hospitals of universal screening for COVID-19 at patient admissions, make it easier to identify the proportion of positive asymptomatic women. which could be, like what happens in the general population, particularly relevant, as well as the proportion of women diagnosed and subsequently resolved of the infection during pregnancy.

The investigators therefore believe it is particularly useful to investigate maternal and fetal outcomes in this new broader scenario, including all pregnancies associated with asymptomatic or symptomatic SARS-CoV-2 infection, found in any gestational period, in order to evaluate in a "real world scenario" "Actual rates of maternal-fetal and neonatal adverse events.