COVID-19 Infection and Fetal-neonatal Outcomes
COVID-19 Infection and Fetal-neonatal Outcomes
COVID-19, the coronavirus responsible for the pandemic that began at the end of 2019 in
 China, 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 epidemic was
 declared a Public Health Emergency of International Interest (PHEIC) by the World Health
 Organization (WHO) on January 30, 2020. In the first phase of emergency worldwide,
 characterized by high morbidity and mortality, scientific interest has been mainly directed
 to the study of the transmission mechanisms of the infection, diagnostic tools and therapies
 for ARDS, especially in elderly and co-morbid patients. 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. 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. Nonetheless, the limited sample size, the main inclusion of cases reported for acute
 respiratory symptoms, the lack of information on previous pathologies potentially capable of
 complicating pregnancy, do not allow for the extrapolation of strong evidence on the course
 of infection in pregnancy. Therefore, the current status of the scientific literature does
 not allow for general and wide-ranging implications. 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
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.
Inclusion Criteria:

 -  Maternal age> 18 years

 -  Women with single or multiple pregnancy at any stage of gestation, with first
 ascertained positivity to the nasopharyngeal swab for SARS-CoV-2 during pregnancy,
 regardless of the presence of symptoms.

 Exclusion Criteria:

 -  age under 18.

 -  Women with an altered state of consciousness, seriously ill, with mental handicaps;

 -  Women with serious systemic diseases that can negatively affect the pregnancy outcome.

 -  Women for whom the treating doctor contraindicates participation in the study.