COVID-19 în sarcină – dificultăţi şi progrese

Introduction

The newly emerging coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading globally at an accelerated rate⁽¹⁾. The emerging and reemerging SARS-CoV-2 infections are a global public concern. SARS-CoV-2 is a new type of enveloped, positive-sense, single-stranded RNA beta-coronavirus. The SARS-CoV-2 genome encodes non-structural proteins (such as 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase), structural proteins (such as spike glycoprotein), and accessory proteins⁽²⁾. The fusion of the viral and cell membranes occurs upon binding of the spike protein on the virion with angiotensin-converting enzyme 2 (ACE2). The fusions allow viral RNA replication inside the host cell and generate new virions able to infect other cells⁽³⁾. The virus spreads through aerosol droplets and has an incubation period of five days (range: 2-14 days)⁽⁴⁾.

Compared with other highly pathogenic coronaviruses SARS and MERS (Severe Acute Respiratory Syndrome and the Middle East Respiratory Syndrome), SARS-CoV-2 appears to be less lethal in pregnancy. Severe maternal morbidity as a result of COVID-19 could not be ruled out, especially in pregnant women with high BMI (>35), when the cardiorespiratory system is affected, or with complications in their pregnancies, such as preeclampsia, gestational diabetes, hypothyroidism, placenta praevia, previous uterine surgeries etc.⁽⁵⁾

Because COVID-19 might increase the risk for pregnancy complications, this review included information about pregnancies affected by the highly transmissible SARS-CoV-2. Once a maternal infection of COVID-19 is suspected or confirmed, the patient should be carefully monitored before and after delivery.

Antenatal care, delivery and breastfeeding

All medical staff treating COVID-19 patients should use personal protective equipment (PPE); this equipment should also be worn during consultation or ultrasound of such patients. The confirmed and suspected cases of COVID-19 should be isolated as soon as possible in a negative-pressure isolation room. A pre-triage based on temperature, fatigue, dry cough, dyspnoea and on a specific questionnaire was developed in order to screen the suspected patients⁽⁶⁾. Abnormal testing includes abnormalities on chest radiographic imaging, lymphopenia, leukopenia, neutrophil-to-lymphocyte ratio  and thrombocytopenia⁽⁴⁾.

The principles of the management of COVID-19 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), fetal and uterine contraction monitoring, early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations⁽⁴⁾.

According to published criteria, the severe infection was defined by dyspnoea reported by patient, respiratory rate >30 per minute, blood oxygen saturation ≤93% on room air, partial pressure of arterial oxygen to fraction of inspired oxygen <300 and/or lung infiltrates >50% within 24 to 48 hours on chest imaging. The critical disease was defined by respiratory failure, septic shock and/or multiple organ dysfunction or failure⁽⁷⁾.

The mechanism whereby viral infection causes multiorgan dysfunction is thought to involve the release of inflammatory cytokines which induce the production of tissue factor and activate thrombin. Given that normal pregnant women have evidence of increased generation of thrombin and a prothrombotic state, as well as an increased intravascular inflammation which is exaggerated in the context of infection, such patients may be at an increased risk for thrombosis when affected by COVID-19. The recommendation was that low-molecular-weight heparin should be considered in such patients⁽⁸⁾.

Pooled data regarding pregnancies reveal a case fatality rate of 18% for SARS and 25% for MERS, respectively; progressive respiratory failure and severe sepsis were the most frequent causes⁽¹⁾, with no confirmed fatalities for SARS-CoV-2⁽⁵⁾.

The early detection and intervention in pregnant women with COVID-19 may reduce the potential fetal complications of the disease, such as miscarriage, intrauterine growth restriction and preterm birth⁽¹⁾.

Evidence for congenital infection is debated. There is a theoretical risk of vertical transmission, similar to that seen in SARS, as the ACE2 receptor is widely expressed in the placenta⁽¹⁾. There are currently no data on first-trimester COVID-19 infection. There is no evidence of the vertical transmission of SARS-CoV-2 when the infection manifests during the third trimester of pregnancy, supported by an absence of viral isolates in the amniotic fluid, cord blood and breast milk. Reports from China suggest, based on a limited assessment of IgM serology and virologic samples in newborns, that the vertical transmission of virus does occur in some cases. Kimberlin and Stagno point out that IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges^(5,9).

Consensus guidance from China advises that delayed cord clamping is not recommended in order to reduce the risk of vertical transmission. They have almost exclusively performed caesarean section births, since vaginal delivery is associated with a low risk of intrapartum SARS-CoV-2 transmission to the fetus.

The newborn should not be fed with breast milk from mothers and should be separated from the mothers affected by COVID-19 for at least 14 day. The American Academy of Pediatrics recommend that COVID-19 positive mothers be separated from their newborns until they are asymptomatic, and until they have two separate virological determinations which demonstrate they are free of infection⁽⁹⁾. The Royal College of Obstetricians and Gynaecologists (RCOG) guidance does not concur, advising that delayed cord clamping should be practiced as normal. If vaginal delivery is permitted, with exposure to maternal secretions and blood, it could be argued that 1 minute of further perfusion via the placenta is unlikely to alter the risk of vertical transmission. RCOG advises against routine separation of mother and newborn and gives guidance on individualized care⁽¹⁰⁾.

As per Italian guidelines, SARS-CoV-2 patients can be considered cured if the symptoms resolve and two tests for SARS-CoV-2 at 24-hour intervals are negative. Virus clearance is defined as viral RNA disappearance from bodily fluids accompanied by the appearance of specific IgG.

Tests following SARS-CoV-2 infection and chest computed tomography (CT)

Before starting to work with SARS-CoV-2 samples, one should consult which precautions, personal protective equipment and protective measures are required⁽¹¹⁾. Specific real-time RT-PCR targeting RNA-dependent RNA polymerase and E genes were used to detect the presence of SARS-CoV-2 in oral swabs according to the World Health Organization guidelines and to Corman et al. protocols. The currently available RT-PCR kits are variable, offering sensitivities ranging between 45% and 60%; thus, especially early in the course of an infection, a repeated testing may be required to make a diagnosis. The reasons for the low sensitivity of PCR may include insensitive nucleic acid detection methods and variations in the accuracy of different tests, low initial viral load or improper clinical sampling⁽¹²⁾. The growing evidence on the limitations of RT-PCR prompts further consideration to improve the ability to detect the coronavirus precisely and to reduce the risk of eliciting false-negative results caused by genome sequence variations. Therefore, the researchers have established multiplex real-time RT-PCR methods with favorable sensitivity for the multitarget detection of coronavirus⁽¹³⁾. Before reverse transcription polymerase chain reaction (RT-PCR) test results are positive, 60-93% of patients have positive chest computed tomography findings consistent with SARS-CoV-2 infection⁽¹⁴⁾. CT imaging revealed ground-glass opacification or consolidation of lung parenchyma⁽¹⁵⁾.

Simple, accurate, rapid and widely accessible point-of-care (POC) tests can identify the women with active infection who present in labor⁽¹⁶⁾, and should help clarify the risks of transmission to the fetus⁽⁹⁾.

A serological assay is critical for identifying potential plasma donors. The use of convalescent plasma may serve as a valuable treatment option for patients with severe COVID-19, especially in the absence of other options⁽¹¹⁾.

The rapid tests are able to simultaneously detect the presence of IgM and IgG in the serum within 15 minutes and can predict the patient’s stage of infection. It is desirable that these rapid tests become more sensitive and specific, in order to quickly identify patients with SARS-CoV-2 and prevent the rapid transmission of the virus⁽¹⁸⁾.

Conclusions

Because the current testing strategies vary substantially and the management guidelines are not uniform, we need better diagnostic tests that are rapid, reliable, validated and widely available^(5,12). There is a concern that the fetuses may be at risk of congenital COVID-19. The existing research suggests that, even though the virus does not reach the fetus, the maternal infection and inflammation which occur in response to the viral infection could affect the developing fetus and even the postnatal life⁽¹⁸⁾.

Regarding the therapeutic options, an extensive repositioning activity of approved drugs has been initiated, based on symptomatic treatment and prevention aimed at reducing transmission⁽³⁾. Efforts have been made to develop vaccines and broad-spectrum anti-coronaviral agents for patients in the current outbreak and future epidemics⁽¹⁹⁾.