Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Describe the epidemiology and typical presentation of COVID-19 in pregnancy.
2. Develop a care plan for pregnant patients with COVID-19 based on the most recent data and available treatment options.
3. Identify patients with severe COVID-19 and understand the maternal and fetal considerations for management.
Background
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began at the end of 2019 and subsequently proceeded to take over 1 million lives globally during the ensuing year.1 This pandemic has introduced a novel challenge to contemporary obstetrics. The implications of an unknown severe respiratory illness caused by a new viral pathogen on pregnancy care and on maternal and neonatal outcomes were completely unknown to obstetric providers at the outset of the pandemic and have gradually been clarified over the course of 2020 and early 2021. Although all health care workers have been required to grapple with the scope and severity of COVID-19, and the health care system has needed to rapidly create inpatient and intensive care capacity while restructuring care delivery to accommodate social distancing and COVID-infected patients, many of these difficulties uniquely impacted the field of obstetrics. These include considerations related to the vulnerability of maternal physiology to severe respiratory illness, the impact of the virus on placental function and fetal development, strategies for management of severe disease in pregnant patients, the safety and efficacy of COVID-19 therapies and prevention strategies in obstetric patients, and the specific care utilization needs of pregnant patients in terms of prenatal care and labor and delivery.
Maternal Physiology and Respiratory Disease
There are significant physiologic and anatomic changes to the respiratory system in pregnancy that can impact manifestations of acute respiratory illnesses. During pregnancy, respiratory rate remains stable but minute ventilation increases due to increases in tidal volume, which are accompanied by a decrease in functional residual capacity.2 Hyperventilation produces a state of compensated respiratory alkalosis [partial pressure of carbon dioxide (Paco2) <=30 mmHg], which is coupled with increased renal excretion of bicarbonate and therefore normal pH.3 These physiologic accommodations are complemented by anatomic changes in chest configuration involving a rise in the diaphragm level and an increase in the transverse diameter of the chest.4
These adaptations to pregnancy, and edema and hyperemia of the upper airway and increased oxygen consumption and CO2 production due to fetal metabolic demands, can predispose pregnant patients to respiratory failure in the setting of an acute infection.5 Pregnancy-related immunocompromise may further render obstetric patients vulnerable to infectious morbidity. Additional respiratory and related comorbidities, such as asthma, cardiovascular disease, hypertension, HIV, diabetes, chronic kidney disease, obesity, and liver dysfunction, may increase risk for worse outcomes.6 Data from prior respiratory pandemics including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and multiple influenza pandemics throughout the 20th and 21st centuries corroborate the increase in morbidity among pregnant patients.7
Clinical Manifestations of COVID-19 in Pregnancy
Symptoms
The SARS-CoV-2 virus has an incubation period of 14 days, although the median time between exposure and symptom onset is only 4 to 5 days.8 Typical symptoms of COVID-19 infection in general include fever and chills, cough, shortness of breath, fatigue, myalgias, headache, loss of taste or smell, sore throat, congestion or rhinorrhea, nausea and vomiting, and diarrhea, but symptomatology varies significantly by infection severity (Table 1). Shortness of breath is the most commonly reported symptom among hospitalized patients. Many infections may also be asymptomatic, although the exact prevalence is unknown in the absence of universal testing. Studies of universal COVID-19 screening on labor and delivery units have reported COVID-19 positivity rates ranging from 4% to 14%, with highly variable rates of asymptomatic infections ranging from 44% to 88% of total positives.9,10
For symptomatic infections, severity has been characterized as: (1) mild-moderate (mild symptoms, mild pneumonia); (2) severe (dyspnea, hypoxia, >50% lung involvement on imaging); and (3) critical (respiratory failure, shock, other multiorgan system failure). The vast majority of infections (80%) are mild to moderate, both in general and in pregnancy specifically.8,11 In pregnancy, common symptoms are similar, favoring cough, sore throat, myalgias, and fever.12 Median time to symptom resolution in pregnancy has been reported at 37 days, with 25% of patients having persistent symptoms 8 or more weeks after onset.13
Laboratory and Radiographic Findings
Laboratory findings in pregnant patients are similar to nonpregnant patients and include elevated C-reactive protein levels, procalcitonin, and transaminases. Some patients manifest leukocytosis, although this can be physiologic in pregnancy, whereas others demonstrate lymphopenia. A minority of patient also demonstrate thrombocytopenia.12 Some of these abnormalities, particularly those of platelet count and liver chemistry, can be associated with other disorders of pregnancy such as preeclampsia and gestational thrombocytopenia, so it is important to maintain these processes on the differential diagnosis. Chest radiography is the mainstay of evaluating patients with significant respiratory symptoms. This may be normal in the setting of mild disease, but will demonstrate ground-glass opacities with posterior or multilobar lung involvement in the setting of COVID-19 pneumonia.14
Medical Complications
Medical complications of COVID-19 infection can impact multiple organ systems.15 Primary manifestations are respiratory disorders including pneumonia, acute respiratory distress syndrome (ARDS), and respiratory failure. Hypercoagulability resulting in thromboembolic complications, cardiac arrhythmias, and acute cardiac and renal injury have all been reported. COVID-19-related psychiatric disease including anxiety, depression, and insomnia and dermatologic manifestations including urticaria and vascular lesions are also known complications. Pregnancy may worsen the course of COVID-19 infection, and symptomatic pregnant patients may be at higher risk of severe disease and death.16 Risk factors for severe disease in pregnancy are similar to the nonpregnant population and include cardiometabolic comorbidities and asthma.11 Reports of the prevalence of medical complications of COVID-19 in pregnancy are biased by capture only of patients who present to care, but have demonstrated pneumonia in 17% of patients and ARDS in 13%.12
Care of Pregnant Patients With COVID-19
Considerations for management of COVID-19 infection in pregnant patients are overall similar to the nonpregnant population, with the additional need to consider timing and mode of delivery and fetal monitoring. First of all, this includes routine precautions to avoid infection such as social distancing and mask wearing when recommended.17 Vaccination in pregnancy to prevent SARS-CoV-2 infection has been discussed later.
Asymptomatic patients and those with mild symptoms should be counseled regarding isolation and infection control measures during the anticipated period of infectivity and assessed for risk of developing severe disease. Expectant management at home with symptomatic treatment is appropriate for these patients, who constitute the majority of pregnant patients with COVID-19.18 Typical supportive treatments include hydration, rest, and acetaminophen as needed to treat fevers. Some outpatients with COVID-19 have been treated with monoclonal antibodies, which have been shown to mitigate disease progression in patients at risk for severe disease.19 There is currently limited information on risks of placental transfer of these medications, but there is also no rationale to withhold them from qualifying patients.
Hospitalization should be considered in patients with major comorbidities such as uncontrolled hypertension or pregnancy complications such as preeclampsia or suspected placental abruption. Signs and symptoms such as high fever (>39[degrees]C), peripheral oxygen saturation less than 95%, and tachypnea (respiratory rate >30/min) may warrant hospital admission, especially in combination. Patients with signs of severe disease such as escalating supplemental oxygen requirements, refractory hypotension, and other evidence of end-organ disease such as kidney or liver failure should be admitted to the hospital and may require intensive care (Table 2). These patients benefit from multidisciplinary care from high-risk pregnancy specialists and critical care teams.20,21
The combined hypercoagulability or pregnancy and of SARS-CoV-2 infection places obstetric patients at increased risk of venous thromboembolism (VTE).22 The rate of VTE in pregnant patients with severe COVID-19 has been reported to be as high of 6%.23 Given these risks, prophylactic anticoagulation is recommended for all pregnant patients admitted to the hospital with COVID-19, which is typically provided in the form of unfractionated heparin or low-molecular-weight heparin.17,24
Another treatment consideration for inpatients with COVID-19 is the use of dexamethasone. Corticosteroids may play a role in managing critical illness in patients with COVID-19 infections with typical doses of 6 mg daily for a 10-day course or until hospital discharge. Dexamethasone dosing can be increased to 6 mg every 12 hours for 48 hours to provide a dose consistent with antenatal corticosteroid dosing for fetal lung maturity if there is a concern for preterm delivery.17,25 This is most appropriate if the patient is past the threshold for viability, generally considered to be around 24 weeks of gestation, with a concern for needing to deliver within the subsequent 2 weeks. There are also numerous antiviral drugs that are being used for treatment of patients with severe COVID-19. The most widely used of these is remdesivir, a novel nucleotide medication that treats a broad range of viruses including Ebola, MERS, and SARS.26 Almost all trials of remdesivir have excluded pregnant patients, but it is being used currently to treat patients with severe COVID-19 in pregnancy.27 Convalescent plasma containing antibodies to SARS-CoV-2 is also being used to treat COVID-19 patients, including in pregnancy.28
Specific obstetric considerations include fetal monitoring and timing and mode of delivery. Decisions regarding fetal monitoring depend on gestational age, maternal status, and a discussion of the risks and benefits of monitoring with the patient. Patients admitted to the hospital with COVID-19 should also be monitored for signs and symptoms of preterm labor and vaginal bleeding and decreased fetal movement. There is a theoretical concern for growth restriction in pregnant patients who have been infected with SARS-CoV-2 as with other SARS infections due to vascular malperfusion that may impact the placenta, but there is limited data to guide management at this time.29 Along these lines, placental pathology has demonstrated acute and chronic intervillous inflammation, chorionic plate and fetal vascular thrombi, and focal avascular villi in some cases.30 In general, delivery is not indicated for maternal status in the event of COVID-19 infection and in the absence of other obstetric indications for delivery. Induction after 39 weeks can be considered to reduce the risk of deteriorating maternal status in the event of SARS-CoV-2 positivity.17 In cases of critical illness, earlier delivery can be considered if there is reason to believe that maternal respiratory status may be improved with delivery.
Additional Considerations for Severe Disease
Critically ill patients with COVID-19-related ARDS may experience severe hypoxemic respiratory failure that can require intubation and mechanical ventilation and rescue measures to support oxygenation.12 These can include extracorporeal membranous oxygenation (ECMO) and prone positioning, and other ventilatory strategies to optimize oxygenation. There is limited experience with ECMO in pregnancy, but existing data have demonstrated that this can be done effectively as a salvage therapy.31 Prone positioning with appropriate padding and support for the gravid uterus may relieve diaphragmatic compression from the abdomen and aortocaval compression from the uterus and can ultimately improve gas exchange in the lungs. There is limited data on proning in pregnancy, but case reports from before and during the COVID-19 pandemic have demonstrated safety and efficacy.32
In general, maternal peripheral oxygen saturation should be maintained at greater than or equal to 95%.33 This correlates with maternal partial pressure of oxygen (Pao2) greater than 70 mm Hg, which enables an appropriate oxygen diffusion gradient to effectively oxygenate the fetal side of the placenta. Ventilator management for ARDS typically involves low tidal volume ventilation and high positive end-expiratory pressure (PEEP). Pregnancy is characterized by a physiologic hypocapnia (low Paco2) to facilitate fetal elimination of carbon dioxide in pregnancy. Permissive hypercapnia may be considered to enable lung protective ventilation (through the use of lower tidal volumes) but should not exceed a Paco2 of 50 to 60 mm Hg. In animal studies, these higher Paco2 levels have been associated with decreased uterine perfusion and increased fetal intracranial pressures.34 High-PEEP ventilation can reduce atelectasis and prevent hyperinflation but can also decrease cardiac preload and output, so a PEEP greater than 10 mm Hg should generally be avoided in pregnancy or, if necessary, involve close maternal and fetal monitoring.
In a large systematic review of 64,000 pregnant patients with COVID-19, intensive care unit (ICU) admission was required in 3.3%, invasive ventilation in 1.6%, and ECMO in 0.11%.12 The overall mortality rate was 0.8%. A report from the Centers for Disease Control and Prevention (CDC) COVID-19 Response Pregnancy and Infant Linked Outcomes Team that included 23,000 pregnant patients and 386,000 nonpregnant female patients of reproductive age with confirmed COVID-19 demonstrated that pregnant patients were at higher risk of ICU admission, requiring mechanical ventilation and ECMO, and death.16
Obstetric Outcomes of COVID-19
Limited data are available at this time regarding obstetric outcomes of SARS-CoV-2 infection in pregnancy. There does not seem to be an increased rate of spontaneous pregnancy loss.35 A large multinational study also demonstrated no change in rates of intrauterine fetal demise, but several studies in the United States alone have demonstrated higher rates of stillbirth in patients with confirmed SARS-CoV-2 infections.23,35,36 The mechanism for this is unknown but may relate to severity of infection and to disruptions in routine prenatal care due to the pandemic. Preterm birth and cesarean delivery rates have been reportedly increased in some studies, but these are likely limited to patients with severe or critical illness.37 The majority of COVID-19-related preterm deliveries have been iatrogenic and related to maternal status, with a small minority relating to concerns for fetal status. There is also a theoretical concern that maternal fever or hypoxemia could alter placental inflammation or blood flow and precipitate preterm labor or preterm premature rupture of membranes. Neonates exposed to SARS-CoV-2 infection in utero have been largely asymptomatic and healthy at birth. Neonatal respiratory distress after exposure to maternal COVID-19 has been generally attributable to prematurity rather than COVID-19 specifically.18 Rates of neonatal mortality have not been increasing in the setting of the pandemic.38
COVID-19 Vaccination in Pregnancy
Several vaccines have been developed and deployed worldwide to facilitate SARS-CoV-2 immunity and to help end the pandemic (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273 mRNA vaccines and JNJ-78436735 vaccine based on recombinant adenovirus vector), but pregnant patients were excluded from all vaccine trials. None of these vaccines use live viruses, which could cause infections and should be avoided in pregnancy. Based on the mechanism of action of these vaccines, neither the vaccine itself nor the related immune activation is thought to be harmful to pregnant patients or fetuses, but safety data are limited. The CDC and the Advisory Committee on Immune Practices together with the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics issued statements advising that COVID-19 vaccinations should not be withheld from pregnant patients.39-41 A recent publication of initial safety data from the CDC's "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System demonstrated no obvious safety concerns among pregnant patients who received the mRNA COVID-19 vaccines.42 Over 35,000 pregnant patients were included in these registries, but more longitudinal follow-up is necessary to fully inform recommendations for COVID-19 immunization in pregnancy with better understanding of maternal and neonatal outcomes.
Conclusion
Information about the COVID-19 pandemic in general, and its impact on pregnancy care and outcomes, continues to evolve rapidly, as the pandemic stretches on and new data emerge. This overview represents the status of the pandemic and the existing knowledge base as of spring 2021. The pandemic has had a dramatic impact on the world's population, resulting in 33 million cases and over 500,000 deaths in the United States alone.43 The health care system has been challenged in new ways to accommodate increased capacity for severely ill patients requiring mechanical ventilation and to innovate strategies to care for patients while containing a pandemic. Pregnancy adds an additional layer of complexity to the pandemic, both in rendering pregnant patients more vulnerable to severe infection and in determining safe and effective ways to deliver prenatal care despite the pandemic. Advocacy for pregnant patients to be included in trials of COVID-19 therapeutics and to have access to vaccination may be enabling life-saving treatment and prevention, although further data are required to fully evaluate risks and benefits. As this data unfolds, recommendations for managing COVID-19 in pregnancy may continue to evolve.
Practice Pearls
* Pregnant patients may have increased potential for severe disease from SARS-CoV-2 infection and should adhere to the most up-to-date recommendations for disease prevention.
* Most pregnant patients infected with SARS-CoV-2 infections will be asymptomatic or experience mild disease. Strategies for managing these patients depend on symptom surveillance and preventing spread.
* Management of severe COVID-19 in pregnancy should make use of multidisciplinary specialists in critical and maternal-fetal care and should involve respiratory and obstetric considerations to optimize maternal and fetal outcomes.
* Potentially effective treatments and prevention strategies should not be withheld from pregnant patients due to theoretical concerns about safety.
* In most cases, timing of delivery in patients currently or previously infected with SARS-CoV-2 should be dictated by typical obstetric indications, although exceptions may be made in critical cases when delivery may improve respiratory status or cases at or near 39 weeks if there is concern for impending clinical deterioration.
REFERENCES