Updates on the Management of Sar-Cov-2 Infection in Pregnancy and Postpartum

Introduction

SARS-CoV-2 is a beta coronavirus with a core and an envelope containing spike glycoproteins, envelope proteins and membrane proteins. It contains a positive strand of RNA as genetic material. The virus belongs to the same subgenus as the severe acute respiratory distress syndrome (SARS) virus. Infection with SARS-CoV-2 leads to COVID-19.

Epidemiology

Source of infection – Bats are the primary source of infection. The role of the intermediate host in the transmission of the coronavirus is unknown.

Pathogenesis

The virus target cells bearing angiotensin-converting enzyme 2 (ACE2) receptors are located primarily in the upper respiratory tract and oropharynx and, to a lesser extent, in the conjunctiva and gastrointestinal tract. The spike protein on the coronavirus envelope binds to the above target receptors and to the host’s trans membrane serine protease 2. This promotes membrane fusion, releasing the viral genome into the host’s cytoplasm, where the virus replicates its genome and synthesizes viral proteins. This is followed by virus assembly, maturation and release. In mild illness, the host immune response (particularly the T cell response) can effectively clear the infection. However, an increased and overwhelming immune response leads to organ damage, severe morbidity and death.

Clinical Features

The incubation period of 5 to 6 days is followed by a symptomatic illness featured by cough, fever, mayalgia, headache, dysopnea, sore throat, diarrhoea, nausea/ vomiting, anosmia, ageusia, rhinorrhoea, chills/rigors, fatigue, confusion, and chest pain.

Diagnosis

• Viral RNA in respiratory swabs can be detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for approximately 17 days (up to 83 days maximum) after the infection. They are not a reliable measure of infectiousness. Viral Culture: Upper respiratory tract viral load peaks in the first week after symptoms appear. After that it gradually decreases. Therefore, culture is rarely positive after 9 days of symptom onset. However, prolonged viral shedding via respiratory droplets may be observed in immunocompromised patients.

Serology: It takes up to 2 weeks for antibodies to the virus spike protein and the nucleocapsid to appear in the serum. Other Laboratory Parameters: The following laboratory markers are deranged in a SARS-CoV-2 infection

• Hemogram – Neutrophilia, lymphopenia (absolute lymphocyte counts below 800/microlitre in severe disease).
• Increased levels of serum lactate, lactate dehydrogenase (more than 245 U/L in severe disease), C-reactive protein (≥ 75 mg/L in severe disease), ferritin (more than 500 mcg/L in severe disease), interleukin-6 (IL6), ACE-2, D-dimer (more than 1 microgram/mL indicates severe disease) and troponin (twice the upper limit of normal).
• Others- Procalcitonin, liver and kidney function tests.

Lung Imaging: Chest X-ray and Chest CT scans- linear and fluffy opacities.

Treatment-General Principles of Management

• The approach to treating of COVID-19 depends on the severity of the disease and the need for supplemental oxygen therapy and ventilatory support.
• Drugs primarily used in the treatment of COVID-19 include:
• Dexamethasone
• Remdesivir - A nucleotide analogue that inhibits RNA- dependent RNA polymerase.
• Immunomodulators – Tocilizumab (a recombinant humanized IgG1monoclonal antibody against interleukin 6 (IL6), and baricitinib (Janus kinase/JAK inhibitor with immunomodulatory and antiviral properties).
• Others
• Ivermectin – An anthelminthic used for the prevention of strongyloidiasis
• Vitamin D, in the presence of vitamin D deficiency
• Convalescent plasma
• Infliximab (TNF inhibitor), abatacept (a selective T-cell stimulatory blocker), anakinra (interleukin-1 inhibitor), viloblimab (monoclonal antibody against complement C5a).

Inpatient Management of Covid-19 Positive Patients

• Testing for COVID-19 – The Government of India recommends that no delivery procedure should be withheld or the patient denied treatment due to the unavailability of testing procedures [3].

• Investigations:
• CRP and D-dimer levels are usually elevated during pregnancy and therefore should not be used to assess disease severity.
• Chest x-rays in pregnant women involve very low levels of radiation exposure (0.01 milligray). CT chest examination should not be withheld when indicated because exposure is low (0.01–0.66 milligray) and is not associated with congenital fetal anomalies or fetal loss. Lung ultrasound can be a useful aid in pregnant women when radiation exposure is a concern.

Prone Position

• For pregnant women at 24 weeks of gestation, padding should be applied at top and bottom positions to relieve aortocaval compression in the prone position. If the woman cannot achieve such a position, a left-lateral position is acceptable.

Drug Therapy for COVID-19 during Pregnancy

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• RNA Polymerase Inhibitor– Remdesivir**
• It is also used to treat Ebola and Marburg virus infections in pregnancy.
• It is not known whether it can cross the placenta, however, no major fetal adverse effects on fetus have been reported from its use.
• Dose: Intravenous 200 mg of the drug is administered on the first day, then 100 mg for a total of 5 to 10 days; it should preferably be started within 10 days of the onset of illness.
• Immunomodulators IL-6 Inhibitor – Tocilizumab and Baricitinib
• Dose: Tocilizumab – Intravenous 8 mg/Kg of the drug is given as a single dose; Baricitinib – Oral 4 mg is given once a day for 14 days or less.
• There are very few data on the use of other cytokine inhibitors in pregnancy like such as Sarilumab (anti- IL-6 inhibitor), Siltuximab (direct IL-6 inhibitor), and Anakinra (IL-1 inhibitor).
• To date, tocilizumab has not been associated with major fetal toxicity.
• Janus kinase (JAK) Inhibitors
• It is not known for certain whether baricitinib can cross the placenta. Studies in animal models have shown the risk of fetal skeletal anomalies and reduced fertility with JAK inhibitors. The patient should be informed about the risks and benefits before starting therapy.
• Tofacitinib can also be used. To date, no drug related fetal toxicity has been reported with this drug.

Supplemental Oxygen Therapy and Ventilation

• In pregnant patients, an oxygen saturation of 95% or more and no less than 92% is desirable.
• A maternal PaO2 of >70 mmHg the desired PaO2 and PCO2 with is required for adequate placental perfusion.
• Patients who cannot maintain oxygenation should receive other methods of ventilation (non-invasive or invasive ventilation). Important points to consider in this regard are:
• PaCO2 should be aimed at the range of 30-32 mmHg as respiratory alkalosis reduces uterine blood flow.
• During ventilation with high positive end-expiratory pressure (PPEP) >10 mmHg, close maternal and fetal monitoring should be performed due to the risk of excessive decreases in cardiac preload and afterload.
• In cases of refractory respiratory failure, extracorporeal membrane oxygenation is indicated during pregnancy.

• Invasive Ventilation is Indicated if, an Oxygen Saturation (SpO2) of 95% is maintained with the Following:
• Oxygen therapy at a rate of 15 L/minute through a mask or nasal cannula.
• Oxygen therapy at a rate greater than 40-50 L/minute through a High Flow Nasal Cannula.
• Oxygen therapy with a venturi mask at a FiO2 of more than 60% [3].
• Airway protection is required due to an altered mental status.

Venous Thromboembolism Prophylaxis

• The risk of venous thromboembolism appears to increase in pregnant women with SARS-CoV-2 infection, particularly in those with severe disease.
• Women should walk and drink enough fluids. Heparin is recommended for the prevention of venous thromboembolism in all, but not in asymptomatic patients unless indicated for other reasons [4].
• Low molecular weight heparin is recommended in prophylactic doses for mild disease and in therapeutic doses for moderate to severe disease. Treatment should be continued for 10 days after hospital discharge or longer if morbidity persists. Heparin may be discontinued in post-caesarean section patients if discharge and home isolation are planned

Steroid Therapy

• Pregnant women with COVID-19 who are receiving supplemental oxygen therapy or mechanical ventilation should receive dexamethasone 6 mg orally or intravenously once daily for 10 days or until discharge, whichever is less.
• If steroid therapy is also indicated for fetal lung maturity, the SMFM recommends administration of the standard fetal lung maturity dose (intravenous dexamethasone 6 mg, every 12 hours for 4 doses) followed by oral/ intravenous dexamethasone 6 mg once daily for 10 days or until discharge, whichever is earlier. However, WHO and the Government of India recommend switching from dexamethasone to hydrocortisone or methylprednisolone (0.5–1 mg/kg in two divided doses for 5 to 10 days) after the standard fetal lung maturity dose is completed to reduce fetal steroid exposure.
• Pregnant women with gestational or pregestational diabetes should have their blood sugar monitored regularly and the target blood glucose level should never exceed 180 mg/dL.
• Inhaled steroid therapy with budesonide can be administered with or without pneumonia or when proinflammatory markers are significantly raised.

Antibiotics

• The Indian government recommends antibiotics to treat bacterial pneumonia or fever that lasts five or more days.

Mode and Timing of Delivery – The Government of India Recommends

• Performing a cesarean section only for obstetric indications. Caesarean section does not play a role in preventing COVID-19 infection in newborns. However, it may be required in severe or critical illness with refractory hypoxemia. The timing of delivery should be individualized based on the gestational age, the severity of the disease, and the presence of obstetric comorbidities.
• Termination of pregnancy should be planned,
• No earlier than 37 to 38 +6/7 weeks in women with asymptomatic or mild illness.
• By ≥ 39 weeks in the presence of moderate illness.
• After stabilisation in cases of severe disease.
• Care should be taken to discontinue low molecular heparin for at least 24 hours and unfractionated heparin for at least 6 hours before planning induction of labour.

Pain Management in Labour

• Epidural analgesia and pudendal blocks can be given

Post-Partum Care

• General recommendations for personal protective practices, hydration and nutrition should be followed.
• The baby’s face and mouth should not be covered with a mask.
• Women should be screened and counselled for mental health problems.
• Breastfeeding, kangaroo mother care and rooming in are considered compatible as long as 10 days have elapsed after a positive RTPCR test in clinically asymptomatic women or after the onset of the first symptoms (an interval of 20 days is recommended for women with severe or critical illness or for women who are severely immunocompromised) and at least 3 days of defervescence without antipyretic. However, the following points should be emphasized:
• Mother wears a mask all the time
• Hand hygiene is maintained at all times
• The nipples are cleaned with a soft damp cloth before each feeding.
• Respiratory etiquette is adhered to
• Expressed breast milk can be given when the mother is unable to feed the baby.

Discharge from Hospital

• When to Discharge?
• Mild disease/asymptomatic illness: Discharge can be planned after 24-48 hours of vaginal delivery and 48-72 hours of caesarean delivery.
• Moderate to severe disease: Plan for discharge when symptoms subside and 10 to 20 days (severe disease/ critical disease/ immunocompromised status) after the onset of symptoms and with at least 72 hours of defervescence without antipyretic use.

What should be Counselled to the Patient at the Time of Discharge from Hospital?

• Danger signs should be duly explained
• The woman should be asked to follow COVID precautions at home
• Details of teleconsultation services, if available, should be provided to the woman
• Routine post-partum care advise should be given including advise on contraception

Conclusion

Infection with SARS-CoV-2 leads to COVID-19. The severity of the illness and the requirement for oxygen therapy and ventilatory support determine how COVID-19 is managed. A small percentage of women may develop serious illness that necessitates close observation, but the majority will only show mild signs of illness and recover without any sequelae. Successful pregnancy outcomes require adherence to protocols for limiting and treating the infection.