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Treating COVID-19 in pregnant patients brings extra challenges, risks.
At the writing of this article in February 2021, severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) cases ranging from asymptomatic infection to fatal respiratory illness have affected more than 100 million individuals and led to more than 2.4 million deaths worldwide.1 Although cases and hospitalizations have decreased from their winter peak, emerging variants threaten to intensify the epidemic.2 It is important to review the clinical evaluation and management of coronavirus disease 2019 (COVID-19) in pregnancy.
Although predominantly transmitted via respiratory droplets, SARS-CoV-2 can be transmitted through the air via aerosolized particles under some circumstances, such as during intubation prior to surgery, and in enclosed spaces.3 Asymptomatic or presymptomatic individuals account for 40% to 50% of transmissions.4
An estimated 95% of infected individuals have asymptomatic or mild illness, with approximately 5% developing severe or critical illness.5 Pregnant individuals with symptomatic COVID-19 may be at higher risk for intensive care unit admission, invasive ventilation, and death.6 Similar to nonpregnant individuals, obesity and diabetes may be risk factors associated with severe COVID-19 illness in pregnant individuals.5,6
Active maternal infection is diagnosed by molecular (also known as polymerase chain reaction [PCR] tests) or antigen detection in nasopharyngeal, nasal, or saliva specimens. Several commercial PCR and antigen tests are available. Rapid antigen tests are inexpensive but not as effective at detecting infection in asymptomatic individuals.
Molecular test result interpretation depends on pretest probability, epidemiologic risk factors, and intended use for diagnostic or screening purposes in health care or congregate living settings. Serologic testing for presence of anti–SARS-CoV-2 immune globulin is used for epidemiologic and seroprevalence studies, but it is not useful for diagnosing active infection. At this time, there is no recommendation by the Centers for Disease Control and Prevention (CDC) for using antibody testing following vaccination to verify immunity.
Symptoms of COVID-19 in pregnant individuals are the same as those in nonpregnant individuals. An incubation period of approximately 5 to 14 days may be followed by fever, respiratory, gastrointestinal, or neurologic symptoms.7,8 Respiratory symptoms can vary from mild upper respiratory symptoms, such as pharyngitis and sneezing, to lower respiratory illness indicated by cough, dyspnea, tachypnea, and decreased oxygen saturation.
Severe to critical respiratory illness manifests approximately 8 to 12 days after symptom onset in 5% to 14% of nonpregnant individuals, and approximately 5% of pregnant individuals.5,9,10 Acute respiratory failure, including acute respiratory distress syndrome (ARDS), is rare. Gastrointestinal symptoms are less common, although loss of smell (anosmia) and taste (ageusia) are reported in more than half of patients.11
The National Institutes of Health (NIH) criteria for classifying the severity of respiratory illness from COVID-19 may generally be applied to pregnant patients, with additional considerations for how pregnancy physiology affects the progression and presentation of symptoms (Table 112). Physiologic changes in the pulmonary function during the third trimester include decreased functional residual capacity by approximately 20% to 30% and increased oxygen consumption by 20%, making lower respiratory infections less well tolerated.
Because the respiratory rate in the third trimester remains relatively unchanged through gestation (with increased tidal volume accounting for increased minute ventilation), an increased respiratory rate above 30 breaths per minute—even if the oxygen saturation on room air is maintained at or slightly above 95%—is a sign of potentially severe respiratory compromise in symptomatic SARS-CoV-2 infection.
Initial evaluation of a pregnant patient with reported mild symptoms such as sore throat or sneezing may be limited and focused. More thorough evaluation is warranted for those with fever, significant respiratory complaints, and systemic symptoms. This includes a thorough history and physical exam with an attempt to understand the timing of symptom onset relative to presentation and progression or improvement of symptoms.
These details help the clinician determine the potential for worsening—ie, a patient with mild clinical illness improving on day 9 or 10 of symptoms is more likely to be near the end of the illness course, whereas a patient with mild, flulike symptoms at day 4 to 5 of illness may worsen and need to be monitored more closely, depending on maternal comorbidities and gestational age.
In those with systemic findings or significant respiratory symptoms, auscultation of the lungs and documentation of oxygen saturation are necessary but not sufficient to assess respiratory status. The physician must also assess and document respiratory rate as well as objective signs of respiratory fatigue or respiratory distress, including accessory muscle use, work of breathing, and ability to speak without interruption due to coughing or dyspnea.
Assessment can be performed at rest and after walking in patients reporting significant symptoms but who appear comfortable at rest and without hypoxia. In these circumstances, the clinician may be uncertain about the need for admission.
For nonpregnant adult patients, a 6-minute walk test is a low-cost assessment of functional status in patients with moderate to severe pulmonary disease.13 Although a full 6-minute walk test may not be feasible for nonlaboring obstetric patients, a brief assessment of ambulation may assist the clinician in determining whether the patient warrants closer observation.
For patients with obvious increased work of breathing, chest pain, or desaturation following minimal ambulation, admission is warranted and supplemental oxygen should be considered. Given that approximately 40% of pregnant patients with initially moderate clinical illness may progress to severe pneumonia, observation for 24 to 48 hours should be considered.5
Unlike other respiratory infections such as influenza, clinical decompensation secondary to COVID-19, if it occurs, happens relatively late in the course of illness.10
Early acute respiratory failure—ie, impaired gas exchange of oxygen and carbon dioxide—in a pregnant patient with COVID-19 should promptly lead to a consultation of maternal-fetal medicine (MFM) and critical care specialists experienced in treating COVID-19. Respiratory failure may be hypoxemic, defined as partial pressure of oxygen (Pao2) less than 60 mm Hg on room air, correlating approximately to an oxygen saturation (SpO2) of less than 90%; or hypercapnic, defined as partial pressure of carbon dioxide (Pco2)greater than 50 mm Hg.
Importantly, a compensated respiratory alkalosis is expected in the third trimester of pregnancy, and if arterial blood gas is obtained and reveals a normal or elevated Pco2, this is an ominous sign of hypercapnic respiratory failure. In the case of a pregnant patient without preexisting cardiac or pulmonary disease admitted with severe pneumonia from COVID-19, early respiratory failure is commonly hypoxemic, although ARDS may develop with resultant hypercapnia due to increased alveolar dead space.
With severe illness, hypoxemia-driven tachypnea (increased respiratory rate) and hyperpnea (increased tidal volume) may lead to more profound hypocapnia (decreased Paco2), which shifts the oxygen-hemoglobin dissociation curve to the left. When this occurs, increased binding affinity for oxygen by hemoglobin results in relative preservation of measured oxygen saturation (Spo2) despite profound hypoxemia (low Pao2).
Whereas this may manifest clinically as “silent hypoxemia” described in elderly patients with COVID-19,14 hypoxemia in pregnancy is unlikely to remain “silent,” and rapid decompensation may occur despite measured Spo2 greater than 90%.
Prompt initial evaluation of a pregnant patient with COVID-19 who presents with cough and dyspnea is key so that appropriate triage takes place in coordination with specialists. This includes a thorough assessment of both oxygenation and ventilation, as well as an awareness of the pitfalls of using Spo2 as a single measure of clinical stability when the patient is tachypneic or describing shortness of breath.
Conditions other than COVID-19 (e.g., pulmonary embolus or pulmonary edema related to obstetric, pulmonary, or cardiac etiologies) should be considered in patients with hypoxia but without significant parenchymal opacities on chest radiography. It is unclear to what extent COVID-19 may exacerbate conditions such as sepsis from acute pyelonephritis or preeclampsia-related pulmonary edema.
For patients who are asymptomatic or with upper respiratory symptoms only, laboratory evaluation beyond COVID-19 testing typically is not necessary. For those with significant respiratory symptoms, systemic illness and fever who present to the hospital, laboratory evaluation following history and physical examination to rule out other causes of infection and hypoxia may be warranted. In our experience managing hospitalized, nonlaboring patients with moderate to severe viral pneumonia, measurement of daily C-reactive protein (CRP) aids in determining the clinical trajectory.
While measurement of CRP performed well in discriminating disease severity and predicting adverse outcomes in nonpregnant patients with COVID-19, the predictive value has not been evaluated in a pregnant population.15
Furthermore, the level of CRP normally rises during pregnancy and with other states of inflammation or infection, so it would be considered less helpful in a laboring or recently delivered patient. Daily evaluation of liver function (aspartate aminotransferase, alanine aminotransferase [ALT]) also is warranted for patients hospitalized with severe illness and in those who receive remdesivir (Veklury).
The Society for Maternal-Fetal Medicine (SMFM) recommends evaluation of ferritin in individuals with fevers higher than 39 °C despite acetaminophen in an effort to identify secondary hemophagocytic lymphohistiocytosis or cytokine storm syndrome, which may have a fulminant course.16
For critically ill patients with suspected respiratory failure, arterial blood gas evaluation may be indicated if clinical improvement is not rapid following initial oxygen supplementation.
During initial evaluation, frequent clinical reassessment with respiratory support titration is more informative than arterial blood gas in awake patients. Obtaining serial arterial blood gas samples may delay escalating care, whereas frequent reassessment of the patient’s initial status and response to oxygen supplementation may help determine whether immediate placement in an intensive care setting or early transfer to a facility with a higher level of care is warranted.
There is no evidence to support measurement of coagulation markers, including D-dimer, in nonhospitalized patients with COVID-19.12 Furthermore, there are limited data supporting the routine use of D-dimer in hospitalized pregnant patients to predict venous thromboembolism (VTE) in the setting of COVID-19, as interpretation may be confounded by physiologic increases during gestation, with certain pregnancy complications, and following delivery.12
Institutional protocols may call for the evaluation of certain laboratory indices as part of a standard panel ordered for patients with COVID-19. In this case, it may be helpful to consult with MFM specialists experienced in caring for pregnant patients hospitalized with COVID-19 before acting on abnormal laboratory results. When VTE is clinically suspected in the evaluation of a patient with COVID-19, appropriate diagnostic imaging studies should be considered.
Chest radiography should be performed for patients with moderate to severe respiratory illness, and repeated if oxygen requirement increases, to evaluate the extent of parenchymal lung disease. Imaging indicative of moderate to severe viral pneumonia reveals opacities in a predominantly peripheral distribution, with a diffuse pattern demonstrated in early ARDS (Figure). CT pulmonary angiography (CTA) should be considered when hypoxia or tachycardia persist despite minimal opacities demonstrated on chest radiography or when clinical suspicion for pulmonary embolism is high. CTA is not routinely indicated for all pregnant patients with COVID-19 and classic symptoms of dyspnea and cough when parenchymal lung disease is demonstrated on chest radiography.
For patients with asymptomatic or mild infection, supportive treatment is appropriate. For moderate illness, inpatient observation may be considered, as up to 40% may progress to severe illness.5 For pregnant patients with severe to critical illness, inpatient treatment involves providing adequate respiratory support, managing comorbid conditions, and coordinating safe delivery in coordination with specialists when indicated.16
Traditional (low-flow) nasal cannula may be initiated for patients with hypoxia but normal to mildly increased respiratory rate (Table 2). Frequent reassessment of both maternal oxygenation and ventilation in consultation with critical care specialists is warranted for patients requiring increasing oxygen supplementation. The goal of respiratory support is to maintain an oxygen saturation of 95% or more in pregnancy and at the same time reduce dyspnea and tachypnea; several oxygen delivery devices may be used.17
If significant mouth breathing is noted, a Venturi mask or nonrebreather mask may be needed to provide more controlled oxygen delivery. For patients with tachypnea or significant work of breathing despite appropriate oxygen supplementation, noninvasive ventilatory support with high-flow nasal cannula (HFNC) may be needed.
Limited evidence in critically ill, nonpregnant patients suggests that HFNC may be more comfortable and potentially offer advantages over noninvasive positive pressure ventilation such as continuous positive airway pressure.18 Prone positioning to improve oxygenation with severe COVID-19 pneumonia has been used during pregnancy, though it may not be well tolerated.19
Managing dyspnea with intermittent intravenous opioids may be considered in coordination with critical care specialists. This may alleviate air hunger and facilitate oxygenation, potentially avoiding the need for intubation.
Controlled intubation is considered when respiratory failure persists or worsens despite increasing support of maternal oxygenation and ventilation. This can be recognized as maximal fraction of inspired oxygen of 100% (with or without nonrebreather added) and increasing flow rate above 40 to 50 Liters per minute using an HFNC device.17
The efficacy of antiviral and biologic agents for COVID-19 in pregnancy remains unclear, and no clinical trials in pregnancy have been conducted. The decision to use currently available therapeutic agents approved under the US Food and Drug Administration’s Emergency Use Authorization (EUA) is made in consultation with MFM and infectious disease experts and in accordance with institutional protocols following a discussion of potential benefits and risks with the patient.12
The NIH recommends that remdesivir, an intravenous nucleotide prodrug of an adenosine analogue, be offered to hospitalized patients with Spo2 of less than 94% on ambient air (at sea level) or those who require supplemental oxygen.20 There currently are no available data to suggest harm in pregnant individuals. SMFM supports offering remdesivir for treatment of COVID-19 in hospitalized individuals who meet criteria, although no clinical trials have demonstrated efficacy in this population.16
Institutions may have protocols for use of EUA-approved therapies and compassionate use medications for COVID-19. For pregnant patients who meet clinical criteria and are offered remdesivir following counseling on the limited data available, daily liver function studies should be followed.
NIH guidelines recommend discontinuing therapy if ALT levels increase to greater than 10 times the upper limit of normal or if signs or symptoms of liver inflammation are observed with ALT increase.12
Other COVID-19 therapies, such as antibody therapies and immunomodulators, have not been studied in pregnancy but may be considered in some individuals in consultation with infectious disease and MFM experts. Monoclonal antibodies bamlanivimab and the combination of casirivimab plus imdevimab are available through EUA to treat outpatients with mild to moderate COVID-19 who are high risk for progressing to severe disease or hospitalization.12
Finally, dexamethasone has been shown to reduce mortality in nonpregnant, hospitalized patients with COVID-19 who require supplemental oxygen.21 The dosing recommended based on the RECOVERY trial (NCT04381936) is 6 mg (intravenous or oral) for 10 days.
SMFM recommends considering twice-daily dosing for 48 hours initially in patients who have an indication for corticosteroids for fetal lung maturity, followed by up to 10 days of daily dosing.16 Antibiotics for respiratory illness are rarely necessary unless bacterial coinfection is strongly suspected.
There is no evidence to support empiric anticoagulation at therapeutic dosing in individuals without suspected or confirmed VTE.16 There is also little evidence to support prophylactic anticoagulation in individuals with asymptomatic or mild infection, whether inpatient or outpatient, without other indications for chemoprophylaxis.
That said, clinicians should adhere to institutional protocols when available. There is an increased risk for VTE in patients with COVID-19, but evidence suggests that this risk is concentrated in hospitalized patients with critical illness.22,23
For pregnant or postpartum individuals hospitalized with severe or critical COVID-19 pneumonia, VTE prophylaxis may be provided with either low molecular weight heparin or unfractionated heparin (if concern for potential delivery or at 35 weeks or later). Even in nonintubated patients, ambulation is typically very limited due to fatigue and supplemental oxygen requirement. For patients hospitalized for obstetric indications who have asymptomatic or mild COVID-19 illness, VTE prophylaxis is not routinely provided outside of other standard indications.
Mild or asymptomatic COVID-19 illness is not an indication for delivery. There is no evidence to support inducing early term labor in patients with mild symptoms and no other indication for delivery. Although earlier evidence suggested potentially higher rates of preterm birth in patients with COVID-19,24 these data may be biased toward inclusion of individuals with severe pneumonia requiring hospitalization. Overall, there does not appear to be a risk of adverse pregnancy outcomes such as preterm birth, except in patients with severe or critical illness.5
Delivery for maternal indication in individuals with preterm gestations should be considered only if adequate maternal oxygen and respiratory support have been provided. Delivery considerations include gestational age, fetal monitoring capabilities, and a discussion of potential benefits versus harms. SMFM provides guidance for considerations regarding delivery timing in pregnant individuals with COVID-19.16
Delivery does not always improve maternal ventilation or prognosis in a critically ill patient, so priority is given to providing adequate respiratory support with frequent reassessment for clinical worsening as long as fetal status is reassuring. If intubation with immediate proning is necessary after maximal noninvasive support is provided without improvement, delivery should be planned for pregnancies at or near term and considered for any patient in the third trimester.
In addition to knowing how to manage COVID-19 illness during pregnancy, clinicians should be prepared to educate patients about evidence-based methods to prevent infection. Nonpharmaceutical interventions such asuniversalmasking, physical distance kept at least 6 feet, and hand hygiene are mainstays for reducing the spread of SARS-COV-2 in both community and health care settings. In health care settings, airborne and contact isolation precautions are used to prevent nosocomial transmission, particularly when invasive procedures are planned.25
Available mRNA vaccines appear to be highly protective against clinical disease in nonpregnant adults,26,27 and the American College of Obstetricians and Gynecologists and SMFM recommend that COVID-19 vaccines be accessible to pregnant and lactating individuals. Animal developmental and reproductive toxicity studies are ongoing, and clinical studies on safety and efficacy of vaccination in pregnancy are anticipated.
As the writing of this article, February 16, 2021, the CDC’s V-safe After-Vaccination Health Checker’s data included more than 30,000 pregnant individuals who have received at least 1 dose of an mRNA vaccine.28 Pregnant and lactating individuals who accept vaccination are counseled that they may experience reactions such as pain, headache, fatigue, myalgia, and low-grade fever. Vaccinated individuals are encouraged to register with V-safe to track local and systemic reactogenicity.
Entering the second year of the pandemic, even with vaccination efforts ongoing and variant strains of SARS-COV-2 becoming more recognized, it is imperative that clinicians remain vigilant and up to date on the evaluation and treatment of a pregnant patient who presents with respiratory symptoms of COVID-19. Clinicians caring for pregnant patients with COVID-19 should be familiar with current CDC guidance and local institutional practices.
They also should consider early consultation with specialists who are most experienced in managing this dynamic illness in pregnancy. As the virus evolves, so must clinicians’ approach to it; this illness likely will not disappear any time soon.