- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04699578
COVID-19 Infection and Fetal-neonatal Outcomes
Impact of COVID-19 Infection on the Course of Pregnancy and Fetal-neonatal Outcomes
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Contact
- Name: Maddalena Morlando, Assistant Professor
- Phone Number: +39 333 426 3110
- Email: madmorlando@gmail.com
Study Contact Backup
- Name: Antonio Schiattarella, MD
- Phone Number: +39 392 16 53 275
- Email: aschiattarella@gmail.com
Study Locations
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-
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Naples, Italy, 80138
- Recruiting
- University of Campania Luigi Vanvitelli
-
Contact:
- Maddalena Morlando, Assistant Professor
- Phone Number: +39 333 426 3110
- Email: madmorlando@gmail.com
-
Contact:
- Antonio Schiattarella, MD
- Phone Number: +39 1653275
- Email: aschiattarella@gmail.com
-
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
All pregnant women at any stage of pregnancy afferent to obstetrics services who tested positive in confirmation tests by nasopharyngeal swab for viral RNA detection through real-time reverse transcriptase - polymerase chain reaction (rRT-PCR) will be included.
Upon confirmation, women will be placed in a specific pregnancy monitoring program that will be defined as "at risk for SARS-COVID2", regardless of participation in this study. For women recruited in the study, no additional instrumental or laboratory investigations are required to be performed in addition to those already provided for in the normal clinical management of COVID-positive patients.
Description
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.
Study Plan
How is the study designed?
Design Details
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Preterm birth rate
Time Frame: Less than 37 weeks gestation
|
Less than 37 weeks gestation
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Gestational age at delivery
Time Frame: Time of delivery
|
Time of delivery
|
|
Preterm birth rates
Time Frame: Less than 24, 28, 34 weeks gestation
|
Less than 24, 28, 34 weeks gestation
|
|
Birth weight
Time Frame: Time of delivery
|
Weight of the baby at the time of delivery
|
Time of delivery
|
Composite adverse neonatal outcomes
Time Frame: Between birth and 28 days of age
|
Number of neonates who will have at least one of the following: necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grade 3 or higher), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), retinopathy (ROP), blood-culture proven sepsis and neonatal death |
Between birth and 28 days of age
|
Maternal outcomes
Time Frame: Between birth and 28 days after the birth
|
Number of mothers who will have at least one of the following: sepsis, histological chorioamnionitis, hysterectomy, intensive care unit admission. |
Between birth and 28 days after the birth
|
Inflammatory markers: coagulation profile, C-reactive protein, glycaemia, ferritinemia
Time Frame: Through study completion, an average of 6 months
|
Through study completion, an average of 6 months
|
Collaborators and Investigators
Investigators
- Study Chair: Antonio Schiattarella, MD, University of Campania "Luigi Vanvitelli"
- Study Director: Nicola Colacurci, Professor, University of Campania "Luigi Vanvitelli"
- Study Chair: Fabiana Savoia, University of Campania "Luigi Vanvitelli"
- Principal Investigator: Alessandra Familiari, Università Cattolica del Sacro Cuore - Dipartimento scienze della salute della donna e del bambino
- Study Director: Antonio Lanzone, Professor, Università Cattolica del Sacro Cuore - Dipartimento scienze della salute della donna e del bambino
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- Disease Attributes
- Pregnancy Complications
- Obstetric Labor Complications
- Obstetric Labor, Premature
- Severe Acute Respiratory Syndrome
- COVID-19
- Infections
- Communicable Diseases
- Premature Birth
- Abortion, Spontaneous
- Placenta Diseases
Other Study ID Numbers
- 8453
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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