Management of COVID-19 infection during pregnancy

“COVID-19” came into our lives in November 2019, and has since created havoc around the globe. This infection is caused by the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2), which is a single chain, enveloped RNA virus1. The index case was reported on 17th November 2019 from Hubei province, China, and it is believed to be of animal origin2. Thereafter, the outbreak of COVID-19 infection has rapidly spread worldwide causing significant morbidity and mortality, including among pregnant mothers.


Introduction
"COVID-19" came into our lives in November 2019, and has since created havoc around the globe. This infection is caused by the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2), which is a single chain, enveloped RNA virus 1 . The index case was reported on 17 th November 2019 from Hubei province, China, and it is believed to be of animal origin 2 . Thereafter, the outbreak of COVID-19 infection has rapidly spread worldwide causing significant morbidity and mortality, including among pregnant mothers.
This was named as "COVID-19" by the WHO (World Health Organization) on 11 th February 2020 and declared as a global pandemic on 11 th March 2020 2 . More than 2.4 billion cases have been reported so far, with nearly 5 million deaths. The pandemic has affected countless more lives as relatives and friends of those who were infected. The economic and psychological impact of the many lockdowns and new health regulations is seen even today.
In Sri Lanka, more than 530,000 people have been infected and nearly 13,700 have died, including 56 maternal deaths. The impact of COVID-19 infection on pregnancy and the fetus has been evaluated Leading article worldwide, and management guidelines have been issued by leading organizations including RCOG (Royal College of Obstetricians and Gynaecologists), ACOG (American College of Obstetricians and Gynaecologists) and FIGO (International Federation of Gynaecology and Obstetrics) 3,4,5 . However, there is no well-established data on management of COVID-19 infection during pregnancy, since it is a new infection. Initially it was believed that pregnancy conferred a higher risk of disease morbidity and mortality, but currently, CDC (Center for Disease Control in USA) states that pregnancy has no additional risk of disease infectivity compared to the non-pregnant population 6 .

Disease transmission
COVID-19 infection is transmitted via respiratory droplets exhaled by infected patients through direct contact or through contaminated surfaces. Vertical transmission from mother to baby is a rare event and it will not depend on mode of delivery, delayed cord clamping or mode of baby feeding 7,8 .

Symptoms and signs
Symptoms and signs of COVID-19 during pregnancy are not different from non-pregnant patients (Table 1).
More than 75% of the patients are asymptomatic and only 15-20% of patients present with symptoms 9 . Among the symptomatic patients, majority have mild symptoms, less than 5% will have the severe disease requiring ICU admissions and less than 1% require invasive ventilatory support 9 .
Majority of the symptomatic patients presented with cough (41%), fever (40%), shortness of breath (21%) and tiredness 10,11,12 . Less common symptoms include sore throat, headache, diarrhea, loss of taste or smell, nausea / vomiting and rhinorrhea 10,11,2 . However, some of these symptoms are difficult to differentiate from symptoms due to normal physiological changes in pregnancy including physiological shortness of breath, nausea/vomiting and fatigue. Therefore, during the assessment of a pregnant mother more specific symptoms should be concerned.
Depending on the symptoms and signs, patients are categorized as asymptomatic, mild disease, moderate disease, severe disease and critical disease ( Table 2).
Severe disease is mostly confined to the third trimester of the pregnancy 9 . Shortness of breath / difficulty in breathing, chest pain and confusion are the alarming symptoms of severe disease. Pregnant mothers with risk factors are more vulnerable to develop severe disease 11 . Risk factors for severe disease include obesity (BMI more than 25), age more than 35 years, Black-Asian origin, being on immunosuppressive drugs, working in healthcare or public facing occupations and presence of comorbidities like diabetes, hypertension, asthma, heart disease, chronic liver disease, chronic lung disease, chronic kidney disease, organ transplantation and malignancies 11 . However, compared to non-pregnant women, pregnant women are more likely to be admitted to the ICU (OR 1.62) and more likely to require intubation and mechanical ventilatory support (OR 1.88) 10 .

Common symptoms Cough
Shortness of breath

RT-PCR
RT-PCR (reverse transcriptase polymerase chain reaction) test is the gold standard for diagnosis of COVID-19 infection in pregnancy 13 . The specificity of RT-PCR test is almost 100% and sensitivity is 70% 14 .
The patients who are suspected to have COVID-19 infection based on symptoms, should undergo RT-PCR test for SARS-CoV-2 RNA using nasopharyngeal swab 13 . If the initial test result is negative but with high suspicion of the disease, RT-PCR test should be repeated.

RAT
RAT (rapid antigen test) is used as a diagnostic test for COVID-19 infection in certain conditions when urgent diagnosis is required, and it also used as a screening test. It is also performed using a nasopharyngeal swab. The main advantage of the test is that it requires only 15-30 minutes to receive the results, whereas RT-PCR takes 48-72 hours. However, it has a low sensitivity and specificity compared to RT-PCR 15 .
Recent meta-analysis has found that sensitivity and specificity of RAT for SARS-CoV-2 virus is 56.2% and 99.5% respectively 16 . Positive predictive value of a positive result of RAT test is high, and it is higher than RT-PCR 15 .

Chest Xray
Chest Xray is particularly important in suspected cases of COVID pneumonia. Findings of chest Xray include patchy multi-focal opacities. However, chest Xray findings of COVID pneumonia can be seen only in advanced disease 17 . There is a clear indication of chest Xray in advanced disease, however risk/benefit ratio must be considered when it is being used in less severe cases.

CT chest
CT chest is considered the imaging method of choice in the diagnosis of COVID pneumonia 18 . This was widely used before the RT-PCR was freely available to diagnose COVID pneumonia. Sensitivity and specificity of CT chest are 97% and 25% respectively with positive predictive value of 65% 19 . Characteristic CT findings help to diagnose COVID pneumonia, including bilateral, subpleural, patchy and multi-focal opacities with ground glass appearance and peripheral consolidation 20,21 . These features can be seen one to three weeks after the onset of infection 17 .

USS chest
Ultrasound scanning of chest can be used to diagnose COVID pneumonia in pregnancy 18 . It has high sensitivity (>90%) and specificity (>95%) 22 . Ultrasound findings of COVID pneumonia includes patchy distribution of interstitial artifactual signs, extended distribution of interstitial artifactual signs and small subpleural consolidation 18 .

MED test
MED (modified exertional desaturation) test is a bed site clinical test used to detect subclinical COVID pneumonia in patients who are not on oxygen therapy and whose oxygen saturation is more than 96%. Patients resting oxygen saturation is measured. The patient is asked to sit and stand for 1minute and, then to rest for 30 seconds. Post exertional oxygen saturation is measured. Positive test result is indicative of subclinical COVID pneumonia.

Treatment
Asymptomatic

Oxygen therapy
Physiological changes in the pregnancy are important to maintain fetal oxygenation, and thus oxygen therapy for patients with COVID-19 in pregnancy is challenging. WHO recommends to maintain oxygen saturation between 92-95% and PaO 2 >70mmHg to minimize fetal hypoxia, and the RCOG recommendation is to maintain the oxygen saturation above 94% 3,23 . Prone ventilation is a well-accepted way to improve oxygenation, and according to available data, it is a safe option in pregnancy 24 .

Steroid therapy
RCOG recommends steroids (oral prednisolone 40 mg once daily or IV hydrocortisone 80 mg twice daily for 10 days or until discharge) if the patient has needed oxygen therapy 3 . Further, low dose dexamethasone therapy has proven benefit of reducing mortality in severe disease. It reduces mortality by 20% in the mothers who receive oxygen therapy and by 33% in the mothers who are ventilated (RECOVERY trial) 25 . Dexamethasone is categorized as a pregnancy category C drug according to UK-MEC (medical eligibility criteria) due to its fetal side effects. However, ACOG recommends the use of dexamethasone in the management of COVID-19 infection in pregnancy when indicated, especially in ICU patients who are mechanically ventilated 4,26 .

Antibiotics
Routine antibiotic administration is not recommended unless a superadded bacterial infection is suspected 3 .

LDA
LDA (low dose aspirin) is recommended to continue in patients with high risk of developing preeclampsia 3 . However, COVID-19 infection is associated with thrombocytopenia in some patients and in such patients, LDA should be discontinued 3 .

Tocilizumab
Tocilizumab is an Interleukin-6 inhibitor, and it is used to inhibit the inflammatory process caused by COVID-19 infection. Its safety in pregnancy and lactation is not well established. However, available observational studies have shown positive effect in reducing mechanical ventilation and death in nonpregnant women 28 . RCOG strongly recommends the use of Tocilizumab (400-800mg single IV infusion) if the CRP value is 75mg/l or more or if the patient is admitted to ICUi-3.

REGEN-COV
REGEN-COV is a combination of monoclonal antibodies -casirivimab and imdevimab. U.S. FDA (United States Food and Drug Administration) authorizes the use of REGEN-COV as a therapy for post exposure prophylaxis of COVID-19 infection, and to prevent severe disease in high risk groups 29 . RCOG strongly recommends the use of REGEN-COV (8g single IV infusion) in patients whose SARS-CoV-2 antibodies are negative 3 .

Remdesivir
Recently developed Remdesivir is a viral RNA polymerase inhibitor. Remdesivir has recently been approved by FDA for use in COVID-19 infection. However, well-established data on the use of Remdesivir in pregnancy is sparse. According to RCOG guidelines, its use is limited to patients who are not improving and those who are deteriorating 3 .

Azithromycin
Azithromycin is not recommended to use in pregnancy due to lack of proven benefit 3 .

Hydroxychloroquine
Hydroxychloroquine is not recommended to use in pregnancy due to lack of proven benefit 3 .

Lopinavir/Ritonavir
Lopinavir/Ritonavir is not recommended to use in pregnancy due to lack of proven benefit 3 .
Further, increased risk of perinatal mental health disorders including maternal depression and anxiety has been identified 3 .

Neonatal complications
Available data do not suggest an increased risk of congenital anomalies, miscarriages or early pregnancy loss due to COVID-19 infection f-1 . However, there is an increased risk of preterm delivery (6%), small for gestational age and still birth 3,31,32,33 . Most of the preterm births are due to iatrogenic causes 31,32,33 . Recent metaanalysis found that there is an increased risk of premature rupture of membranes and fetal hypoperfusion 34 .

Vertical transmission
There is no conclusive evidence on transplacental transmission of the disease, and it is thought to be rare. Water birth is not contraindicated for asymptomatic patients. However it is not recommended for symptomatic patients 3 .

Postnatal care
Routine postnatal care should be offered to all patients with COVID-19 infection 3 . Both mother and baby should be managed together unless there is a maternal or neonatal indication.

Breast feeding
Breastfeeding should be encouraged since benefits of breastfeeding outweigh the potential risk of neonatal infection via breast milk. There is no proven evidence of transmitting the virus via breastmilk 35 . There is a risk of transmitting the disease from mother to neonate via direct contact. However, this can be minimized by wearing a facemask and by good hand hygiene 35 . In case of expressed breastmilk, a breast pump is recommended with careful cleaning of the pump before and after each use 35 .

Summary
Majority of the pregnant mothers infected with COVID-19 infection are asymptomatic. Among the symptomatic patients, majority have mild symptoms. Both these groups can be managed in a home-based setting. However, supervised observation and effective communication should be maintained to identify alarming symptoms and signs early. Patients with moderate to severe disease should be managed at hospital-based setting and close monitoring should be done to identify disease progression, development of multi organ failure and critical disease.
Early identification of alarming symptoms and signs, early hospitalization of the patients with moderate to severe disease, early intubation and mechanical ventilation and effective MDT management are the key steps in reducing maternal morbidity and mortality associated with COVID-19 infection.