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.