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COVID-19 in pregnancy and the puerperium: A review for emergency physicians

Published:October 31, 2020DOI:https://doi.org/10.1016/j.ajem.2020.10.055

      Abstract

      Background

      Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel virus responsible for causing the novel coronavirus disease of 2019 (COVID-19).

      Objective

      This article discusses the clinical manifestations of COVID-19 in pregnant patients, the effects of pregnancy on the course of COVID-19 disease, and the impact of COVID-19 on pregnancy outcomes.

      Discussion

      The physiological and mechanical changes associated with pregnancy increase maternal susceptibility to infections and complicate intubation and mechanical ventilation. The most common symptoms of COVID-19 in pregnant patients are cough and fever, although many infected individuals are asymptomatic. The majority of pregnant women diagnosed with COVID-19 disease have a mild course of illness and will recover without needing to deliver, but the risks of critical illness and need for mechanical ventilation are increased compared to the general population. Risk factors for death and severe disease include obesity, diabetes, and maternal age > 40 years. Women in their third trimester have the highest risk for critical illness, intensive care unit admission, and need for mechanical ventilation. Adverse fetal outcomes of maternal COVID-19 infection include increased risk of miscarriage, prematurity, and fetal growth restriction. Vertical transmission of SARS-CoV-2 is possible but has not been conclusively proven.

      Conclusions

      COVID-19 is a potentially deadly infection, but data are limited concerning the pregnant population. Pregnant patients appear to present similarly to the general population, with fever and cough being the most reported symptoms in studies. Knowledge of these presentations and outcomes can assist clinicians caring for these patients.

      Keywords

      1. Introduction

      Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel enveloped ribonucleic acid (RNA) virus responsible for causing the novel coronavirus disease of 2019 (COVID-19), a multi-system disease ranging in severity from asymptomatic to fatal [
      • Wang C.
      • Horby P.W.
      • Hayden F.G.
      • Gao G.F.
      A novel coronavirus outbreak of global health concern.
      ]. In March 2020, the World Health Organization (WHO) declared the outbreak of COVID-19 a pandemic []. Emergency clinicians are frequently the first point of healthcare contact for patients presenting with COVID-19. As such, the burden of counseling on the course of illness, preventative measures, and treatment falls commonly on providers in the emergency department (ED). Additionally, many providers caring for patients infected with SARS-CoV-2 are pregnant or recently-pregnant, and understanding the risks of exposure to COVID-19 can aid allocation of resources and guide protocols to protect them. Pregnant patients are an especially vulnerable population in the time of the COVID-19 pandemic, and clinician knowledge regarding the disease and its effects on pregnancy can aid emergency physicians in treatment planning and patient counseling.

      2. Methods

      This narrative review provides a focused overview of COVID-19 in pregnancy for emergency clinicians. The authors searched PubMed and Google Scholar for articles using the Medical Subject Heading (MeSH) compliant keywords “pregnancy” and “COVID-19” or “coronavirus” or “SARS-CoV-2”. The search was conducted from database inception to September 30, 2020. PubMed yielded 1066 articles, and Google Scholar yielded 13,400 articles. Authors evaluated case reports and series, retrospective and prospective studies, systematic reviews and meta-analyses, and other narrative reviews. Authors also reviewed guidelines and supporting citations of included articles. The literature search was restricted to studies published in English, with focus on the emergency medicine and critical care literature. Authors decided which studies to include for the review by consensus. When available, systematic reviews and meta-analyses were preferentially selected. These were followed sequentially by randomized controlled trials, prospective studies, retrospective studies, case reports, and other narrative reviews when alternate data were not available. A total of 59 resources were selected for inclusion in this narrative review.

      3. Discussion

      3.1 Pathophysiology of respiratory illnesses and other coronaviruses in pregnancy

      The physiological and mechanical changes associated with pregnancy increase maternal susceptibility to infections in general. Pregnancy is a state of relative immunosuppression, caused by a change in the maternal immune system to prevent rejection of the semiallogenic fetus [
      • Mathad J.S.
      • Gupta A.
      Pulmonary infections in pregnancy.
      ]. This occurs through a hormone-mediated shift from a primarily type 1 T helper cell response to a type 2 T helper cell response, which is more anti-inflammatory in nature [
      • Mathad J.S.
      • Gupta A.
      Pulmonary infections in pregnancy.
      ]. Increased estriol levels also decrease CD4+ and CD8+ T cells, suppress inflammatory cytokine production, and promote the release of anti-inflammatory cytokines [
      • Mathad J.S.
      • Gupta A.
      Pulmonary infections in pregnancy.
      ]. These immunologic shifts, and physiologic changes discussed later, predispose pregnant individuals to a more severe and protracted disease course with respiratory infections [
      • Mathad J.S.
      • Gupta A.
      Pulmonary infections in pregnancy.
      ].
      This phenomenon has been well documented with coronavirus infections in the past [
      • Perlman S.
      Another decade, another coronavirus.
      ]. Given the relative novelty of the SARS-CoV-2 virus, data regarding its specific pathophysiologic impact in pregnancy are limited. However, recent coronavirus epidemics caused by the Middle Eastern Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV-1) viruses in 2003 and 2012, respectively, can provide valuable informatin [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ,
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. MERS-CoV and SARS-CoV-1 appear to cause more severe disease in pregnant patients compared to SARS-CoV-2 [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. A 2020 meta-analysis calculated a mortality rate approaching 25–30% in pregnant women with severe SARS-CoV-1 and MERS-CoV, whereas current estimates for SARS-CoV-2 mortality in pregnant women are less than 2% [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ].
      Data from SARS-CoV-1 and MERS-CoV can also inform the response to SARS-CoV-2 until more specific data are available. In examining the SARS-CoV-1 and MERS-CoV outbreaks, significant morbidity and mortality were most common among patients in the second and third trimesters of pregnancy [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ]. Adverse outcomes included miscarriage, small for gestational age neonates, and prematurity [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ]. Fever, cough, and fatigue were the most commonly reported symptoms with both SARS-CoV-1 and MERS-CoV [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. The most common laboratory abnormalities were lymphocytopenia, elevated C-reactive protein (CRP), and leukopenia [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. A meta-analysis of pregnant women hospitalized for infection with SARS-CoV-1, MERS-CoV, or SARS-CoV-2 noted that 90% of these patients demonstrated radiographic evidence of pneumonia either on plain x-ray or computed tomography (CT), even when asymptomatic [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. This meta-analysis also noted an increased rate of preterm birth, caesarean delivery, neonatal intensive care unit (NICU) admission, and preeclampsia in women diagnosed with any of the three coronaviruses compared to the general population [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. There have been no documented cases of vertical transmission of SARS-CoV-1 or MERS-CoV [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ,
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ].

      3.2 Clinical manifestations of COVID-19 in pregnancy

      Testing in non-pregnant individuals most commonly occurs when they present with symptoms or a concerning contact history, whereas pregnant individuals are often tested for COVID-19 when presenting for care for pregnancy or reasons unrelated to the COVID-19 outbreak [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ,
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. A living systematic review of 28 studies including 11,432 patients found that 1 in 10 pregnant or recently-pregnant women presenting or admitted to the hospital tested positive for COVID-19 [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. Of these, three quarters were asymptomatic, and one in twenty asymptomatic pregnant women presenting or admitted to the hospital tested positive for COVID-19 [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. Similar to the general population, the predominant features of symptomatic COVID-19 in pregnant patients were fever, cough, dyspnea, and lymphopenia [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. The largest cohort study to date reported cough and fever as the most common symptoms in pregnant women presenting with COVID-19, 33% and 29%, respectively, rates similar to the 40% and 39% reported in the Allotey et al. cohort study [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. Compared to non-pregnant women of reproductive age, pregnant or recently-pregnant women with COVID-19 were less likely to report fever or myalgias [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. A French cohort study suggested that the presence of gastrointestinal symptoms was associated with more severe disease [
      • Cohen J.
      • Vignaux O.
      • Jacquemard F.
      Covid-19 in pregnant women: general data from a French national survey.
      ]. Symptoms do not appear to differ based on gestational age at the time of presentation [
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ].
      Both leukocytosis and leukopenia occur commonly in pregnant patients with COVID-19. A small case study noted that leukocytosis, lymphopenia, increased neutrophil ratio, and normal presenting temperature were more common in pregnant versus nonpregnant women with COVID-19 [
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ]. In contrast, a later meta-analysis found leukopenia to be the most common laboratory abnormality in these patients (66.1%) but supported the finding of lymphopenia as a common abnormality (48.3%) [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. Other common laboratory abnormalities reported in the literature include an elevated CRP, D-dimer, and lactate dehydrogenase (LDH) [
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. The most common CT finding of COVID-19 pneumonia in pregnant patients included ground glass opacities and bilateral infiltrates [
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ,
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. A meta-analysis of 42 studies comprising 247 pregnant patients with COVID-19 found that focal unilateral or bilateral ground-glass opacities were the most common imaging findings in mild or asymptomatic disease, while all patients with critical illness had diffuse bilateral ground-glass opacities with subpleural involvement and pleural effusion on imaging [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ,
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ]. This study found abnormal imaging in 89% of patients, 8.7% of whom were asymptomatic at the time of imaging [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. This is similar to studies including patients with SARS-CoV-1 and MERS-CoV, which showed that abnormal imaging findings were common in asymptomatic pregnant patients [
      • Galang R.R.
      • Chang K.
      • Strid P.
      • et al.
      Severe coronavirus infections in pregnancy: a systematic review.
      ,
      • Diriba K.
      • Awulachew E.
      • Getu E.
      The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis.
      ].
      Given the prevalence of community spread of SARS-CoV-2 and relatively high rates of positive testing in otherwise asymptomatic individuals, it is important to not fall prey to premature closure in pregnant patients who test positive for COVID-19 [
      • Kim G.U.
      • Kim M.J.
      • Ra S.H.
      • et al.
      Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19.
      ]. Many conditions common to pregnancy can present with fever, cough, or dyspnea, and COVID-19 increases risk for several common pregnancy conditions, including pre-eclampsia and pulmonary embolism (PE) [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. The differential diagnosis for the symptoms of COVID-19 in pregnancy is broad and includes PE, cardiomyopathy, pleural or pericardial effusion, pre-eclampsia, gestational rhinitis, physiologic dyspnea, and other etiologies of viral/bacterial pneumonia. Common complications of pregnancy and the puerperium should remain high on the differential for these patients, regardless of the results of COVID-19 testing. Patients should be evaluated for these common conditions based on their history and examination. Table 1 demonstrates the most common signs and symptoms, laboratory findings, and imaging findings in pregnant patients with COVID-19.
      Table 1Clinical Manifestations of COVID-19 in Pregnancy [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]
      Signs/symptomsLaboratory findingsImaging findings
      Cough↑/↓ LeukocytesUnilateral or bilateral ground-glass opacities
      Fever↓ Lymphocytes
      Pleural effusions
      Dyspnea↑ CRP
      Myalgias↑ LDH
      Anosmia / dysgeusia↑ D-dimer
      The combination of elevated D-dimer and IL-6 is a poor prognostic indicator [11].
      Nausea↑ IL-6
      The combination of elevated D-dimer and IL-6 is a poor prognostic indicator [11].
      Vomiting
      Diarrhea
      a The combination of elevated D-dimer and IL-6 is a poor prognostic indicator [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ].

      3.3 Clinical course and outcomes of COVID-19 in pregnancy

      Data on the course of COVID-19 in pregnant women are mixed. Small international case series suggest a similar course of illness in pregnant and non-pregnant women [
      • Cohen J.
      • Vignaux O.
      • Jacquemard F.
      Covid-19 in pregnant women: general data from a French national survey.
      ,
      • Hirshberg A.
      • Kern-Goldberger A.R.
      • Levine L.D.
      • et al.
      Care of critically ill pregnant patients with coronavirus disease 2019: a case series.
      ,
      • Yan J.
      • Guo J.
      • Fan C.
      • et al.
      Coronavirus disease 2019 in pregnant women: a report based on 116 cases.
      ,
      • Ferrazzi E.
      • Frigerio L.
      • Savasi V.
      • et al.
      Mode of delivery and clinical findings in COVID-19 infected pregnant women in northern Italy.
      ,
      • Salvatori G.
      • de Rose D.U.
      • Concato C.
      • et al.
      Managing COVID-19-positive maternal-infant dyads: an Italian experience.
      ]. Most studies suggest that critical illness is rare in pregnant patients but slightly increased when compared to the general population [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Hirshberg A.
      • Kern-Goldberger A.R.
      • Levine L.D.
      • et al.
      Care of critically ill pregnant patients with coronavirus disease 2019: a case series.
      ,
      • San-Juan R.
      • Barbero P.
      • Fernández-Ruiz M.
      • et al.
      Incidence and clinical profiles of COVID-19 pneumonia in pregnant women: a single-Centre cohort study from Spain.
      ,
      • Schwartz D.A.
      An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes.
      ]. One study reported that approximately 90% of pregnant women diagnosed with COVID-19 disease recovered without needing to deliver [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. A meta-analysis of 637 pregnant women with COVID-19 found that 76.5% of patients had mild disease, 15% had severe disease, and 7.7% had critical disease at the time of admission (Table 2) [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Of those with mild disease, approximately 3% went on to develop severe or critical infection [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Those patients with severe or critical disease accounted for the majority of poor maternal and neonatal outcomes, including maternal death, stillbirth, neonatal death, and NICU admission [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ].
      Table 2COVID-19 Severity by Clinical Findings [
      • Ellington S.
      • Strid P.
      • Tong V.T.
      • et al.
      Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020.
      ,
      ]
      ClassificationDefinition
      Asymptomatic-Positive SARS-CoV-2 testing but no symptoms
      Mild-Fever, cough, headache but no shortness of breath, dyspnea, or abnormal imaging
      Moderate-Clinical or radiographic evidence of mild pneumonia

      O2 saturation >93% on room air at sea level
      Severe-Dyspnea, respiratory rate ≥ 30/ min, O2 saturation ≤ 93%, P:F ratio <300, or >50% lung infiltrates
      Critical-Respiratory failure, septic shock, and/or multiorgan dysfunction
      Other studies also demonstrate severe outcomes in pregnant patients with COVID-19. While estimated mortality rates for pregnant patients with COVID-19 are 0.6–2%, comparable to the general population, those with critical disease at the time of presentation account for the vast majority of deaths secondary to COVID-19 [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. A recent study found an increased risk of severe illness and mechanical ventilation in pregnant women compared to their non-pregnant counterparts when adjusted for age, race, and co-morbidities [
      • Ellington S.
      • Strid P.
      • Tong V.T.
      • et al.
      Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020.
      ]. The rate of intensive care admission rises with increasing gestational age, with one study reporting more than 90% of pregnant patients requiring ICU in their third trimester [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Data suggest 40% of pregnant patients who died from COVID-19 had obesity, diabetes, or maternal age greater than or equal to 40 years [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • San-Juan R.
      • Barbero P.
      • Fernández-Ruiz M.
      • et al.
      Incidence and clinical profiles of COVID-19 pneumonia in pregnant women: a single-Centre cohort study from Spain.
      ,
      • Ellington S.
      • Strid P.
      • Tong V.T.
      • et al.
      Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020.
      ]. Complications of severe illness include the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), preterm delivery, and COVID-related cardiomyopathy [
      • Ellington S.
      • Strid P.
      • Tong V.T.
      • et al.
      Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020.
      ]. Pregnant women with COVID-19 were more likely to require mechanical ventilation and admission to an ICU. Increased maternal age, high body mass index, pre-existing hypertension, and pre-existing diabetes were associated with severe COVID-19, and the presence of maternal co-morbidities was a risk factor for ICU admission and mechanical ventilation [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ,
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. The severity of maternal disease correlated with risk for NICU admission or neonatal death [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. The combination of elevated D-dimer and interleukin-6 levels was likewise associated with more severe disease and found to be present in 60% of severely ill and 80% of critically ill pregnant women with COVID-19, respectively [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Unfortunately, data on baseline levels of these labs in pregnancy are limited, making comparisons difficult. Additionally, COVID-19 is associated with the development of cardiomyopathy in 7–33% of the general population [
      • Clerkin K.J.
      • Fried J.A.
      • Raikhelkar J.
      • et al.
      COVID-19 and cardiovascular disease.
      ,
      • Thompson J.L.
      • Nguyen L.M.
      • Noble K.N.
      • Aronoff D.M.
      COVID-19-related disease severity in pregnancy.
      ]. Data on COVID-19 cardiomyopathy in pregnancy are limited, as there is only one small case series reporting on two pregnant patients who developed cardiomyopathy with COVID-19 [
      • Juusela A.
      • Nazir M.
      • Gimovsky M.
      Two cases of coronavirus 2019–related cardiomyopathy in pregnancy.
      ]. Due to lack of data, it is uncertain whether the risk of COVID-19-related cardiomyopathy is increased in pregnant patients compared to the general population.

      3.4 Effects of COVID-19 on pregnancy and the perinatal period

      The PRIORITY study, which included 179 infants born to COVID-positive mothers and 84 infants born to COVID-negative mothers, found no increased risk of preterm birth, NICU admission, and respiratory disease in the COVID-positive cohort, although NICU admission and preterm birth were increased in the sub-group of mothers testing positive 0–14 days before delivery [,
      • Perlman S.
      Another decade, another coronavirus.
      ,
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ,
      • Cohen J.
      • Vignaux O.
      • Jacquemard F.
      Covid-19 in pregnant women: general data from a French national survey.
      ,
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Hirshberg A.
      • Kern-Goldberger A.R.
      • Levine L.D.
      • et al.
      Care of critically ill pregnant patients with coronavirus disease 2019: a case series.
      ,
      • Yan J.
      • Guo J.
      • Fan C.
      • et al.
      Coronavirus disease 2019 in pregnant women: a report based on 116 cases.
      ,
      • Ferrazzi E.
      • Frigerio L.
      • Savasi V.
      • et al.
      Mode of delivery and clinical findings in COVID-19 infected pregnant women in northern Italy.
      ,
      • Schwartz D.A.
      An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes.
      ,
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ,
      • Fenizia C.
      • Biasin M.
      • Cetin I.
      • et al.
      Analysis of SARS-CoV-2 vertical transmission during pregnancy.
      ,
      • Carosso A.
      • Cosma S.
      • Serafini P.
      • Benedetto C.
      • Mahmood T.
      How to reduce the potential risk of vertical transmission of SARS-CoV-2 during vaginal delivery?.
      ]. The largest cohort study to date followed the courses of 242 COVID-19 positive pregnant women and their 248 infants through the third trimester of pregnancy and one month postpartum [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Notable outcomes of this study include a higher rate of caesarean delivery and premature birth in patients hospitalized due to COVID-19 symptoms, findings that have been replicated in several cohort studies and meta-analyses [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. It is uncertain whether the higher rate of prematurity derives from a need to deliver secondary to COVID-19 related maternal complications or from effects of the disease on the pregnancy. Rates of preterm birth and caesarean delivery are increased in COVID-19 patients regardless of the severity of disease, suggesting that these outcomes may be iatrogenic. One meta-analysis found that preterm delivery occurred in approximately one third of patients with COVID-19 [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Of these, 40% were early preterm deliveries (occurring between 24 weeks and 33 weeks 6 days gestation), and 60% were late preterm deliveries (occurring between 34 weeks and 36 weeks 6 days gestation) [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Rates of caesarean delivery are extremely high in COVID-19 patients in this meta-analysis, with reported rates of nearly 85% [
      • Fenizia C.
      • Biasin M.
      • Cetin I.
      • et al.
      Analysis of SARS-CoV-2 vertical transmission during pregnancy.
      ,
      • Carosso A.
      • Cosma S.
      • Serafini P.
      • Benedetto C.
      • Mahmood T.
      How to reduce the potential risk of vertical transmission of SARS-CoV-2 during vaginal delivery?.
      ]. Notably, they also found that the only documented indication for caesarean delivery in approximately half of these cases was maternal COVID-19, again suggesting that this effect may be iatrogenic in nature [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ].
      Data on fetal complications from COVID-19 are limited. Evidence suggests that miscarriage is more common in patients who became ill in the first trimester compared to the second trimester, with rates of 16.1% and 3.5%, respectively [
      • Baergen R.N.
      • Heller D.S.
      Placental pathology in Covid-19 positive mothers: preliminary findings.
      ,
      • Chen S.
      • Huang B.
      • Luo D.J.
      • et al.
      Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases.
      ,
      • Kuhrt K.
      • McMicking J.
      • Nanda S.
      • Nelson-Piercy C.
      • Shennan A.
      Placental abruption in a twin pregnancy at 32 weeks’ gestation complicated by coronavirus disease 2019 without vertical transmission to the babies.
      ,
      • Baud D.
      • Greub G.
      • Favre G.
      • et al.
      Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection.
      ]. While direct data are not available, abnormal fetal growth due to placental insufficiency is a concern in pregnant patients due to documented uteroplacental vascular malperfusion, intervillous inflammation, and thrombosis of fetal intervillous vessels in maternal COVID-19 infection [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. This concern derives from 4 studies reporting on the histopathological examinations of 14 placentas from patients with clinically mild COVID-19 which found occlusive fibrin deposition and non-occlusive thrombi with placental hypoperfusion in all specimens [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Knight Dphil M.
      • Bunch K.
      • Vousden N.
      • et al.
      Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study.
      ]. Half of these cases resulted in preterm delivery, and one case each of placental abruption, second-trimester miscarriage, and small for gestational age infant were also reported [
      ,
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ,
      • Fenizia C.
      • Biasin M.
      • Cetin I.
      • et al.
      Analysis of SARS-CoV-2 vertical transmission during pregnancy.
      ,
      • Carosso A.
      • Cosma S.
      • Serafini P.
      • Benedetto C.
      • Mahmood T.
      How to reduce the potential risk of vertical transmission of SARS-CoV-2 during vaginal delivery?.
      ].
      Neonates whose mothers were admitted for the treatment of COVID-19 infection had an odds ratio of 3 of prematurity, regardless of the severity of maternal disease [
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ]. Spontaneous preterm labor is not increased compared to the general population, and caesarean sections account for nearly all the preterm deliveries reported [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ]. Accordingly, most of the complications in neonates born to COVID-19 positive mothers are a result of prematurity rather than COVID-19 infection. Infants with mothers who tested positive closer to delivery were more likely to be admitted to the NICU than those with mothers who tested positive two or more weeks prior to delivery [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. Stillbirths and neonatal death rates are not increased compared to the general population [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. In a recent cohort study, nearly a tenth of the neonates born to COVID-19 positive mothers presented to the ED in the first month of life [
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ]. None tested positive for COVID-19 [
      • Chen H.
      • Guo J.
      • Wang C.
      • et al.
      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
      ,
      • Wei M.
      • Yuan J.
      • Liu Y.
      • Fu T.
      • Yu X.
      • Zhang Z.J.
      Novel coronavirus infection in hospitalized infants under 1 year of age in China.
      ,
      • Zhu H.
      • Wang L.
      • Fang C.
      • et al.
      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      ,
      • Zeng L.
      • Xia S.
      • Yuan W.
      • et al.
      Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.
      ]. This is in line with the findings of the PRIORITY study, which reported no cases of pneumonia or lower respiratory disease in neonates born to COVID-positive mothers at 6–8 weeks of age [
      • Wei M.
      • Yuan J.
      • Liu Y.
      • Fu T.
      • Yu X.
      • Zhang Z.J.
      Novel coronavirus infection in hospitalized infants under 1 year of age in China.
      ,
      • Zeng L.
      • Xia S.
      • Yuan W.
      • et al.
      Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.
      ]. Several case series report mild symptoms in neonates diagnosed with COVID-19 at or shortly after birth [
      • Chen H.
      • Guo J.
      • Wang C.
      • et al.
      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
      ,
      • Wei M.
      • Yuan J.
      • Liu Y.
      • Fu T.
      • Yu X.
      • Zhang Z.J.
      Novel coronavirus infection in hospitalized infants under 1 year of age in China.
      ,
      • Zhu H.
      • Wang L.
      • Fang C.
      • et al.
      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      ,
      • Zeng L.
      • Xia S.
      • Yuan W.
      • et al.
      Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.
      ]. The most common findings of COVID-19 in neonates are fever, pneumonia, cyanosis, respiratory distress, and feeding intolerance [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. The majority of patients in these case series had mild symptoms and favorable outcomes, and most complications were related to prematurity and sepsis, rather than SARS-CoV-2 [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ].
      Vertical transmission of SARS-CoV-2 remains widely debated. No cases of vertical or horizontal transmission were found in the Marin Gabriel at al study [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ]. However, Turan et al. reported in their meta-analysis that 2% of infants born to mothers with COVID-19 tested positive 16–24 h after birth by naso- and oropharyngeal swabs; the PRIORITY study reported a similar positivity rate of 1.1% in infants born to COVID-19 infected mothers [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Flaherman V.J.
      • Afshar Y.
      • Boscardin J.
      • et al.
      Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.
      ]. SARS-CoV-2 virions have also been visualized in the syncytiotrophoblasts and microvilli of the placenta, suggesting that transplacental transfer may be possible [
      • Tobaiqy M.
      • Qashqary M.
      • Al-Dahery S.
      • et al.
      Therapeutic management of patients with COVID-19: a systematic review.
      ]. Both Ig-G and Ig-M antibodies against COVID-19 have been found in seronegative neonates born to COVID-19 infected mothers [
      • Carosso A.
      • Cosma S.
      • Serafini P.
      • Benedetto C.
      • Mahmood T.
      How to reduce the potential risk of vertical transmission of SARS-CoV-2 during vaginal delivery?.
      ,
      • Baergen R.N.
      • Heller D.S.
      Placental pathology in Covid-19 positive mothers: preliminary findings.
      ]. This is notable because Ig-M antibodies cannot cross the placenta, suggesting a fetal immune response against the virus in neonates born to an infected mother. While SARS-CoV-2 has been isolated from maternal vaginal mucosa and stool samples, it has also been isolated from cord blood, placenta, and amniotic fluid, and there are no data to suggest that caesarean delivery is safer or reduces the risk of vertical transmission of SARS-CoV-2 in these patients [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ].

      3.5 COVID treatments in pregnancy

      Human data on the effects of COVID-19 treatments on pregnancy are limited. Current treatments for patients with COVID-19 include dexamethasone, convalescent plasma, and the antiviral medication remdesivir [
      • Tobaiqy M.
      • Qashqary M.
      • Al-Dahery S.
      • et al.
      Therapeutic management of patients with COVID-19: a systematic review.
      ]. The RECOVERY trial, which demonstrated a mortality benefit of dexamethasone in patients with COVID-19 who required respiratory support, did include pregnant and breastfeeding patients and reported no pregnancy-associated adverse outcomes [
      • Horby P.
      • Lim W.S.
      • Emberson J.
      • et al.
      Dexamethasone for COVID-19-Preliminary Report Effect of Dexamethasone in Hospitalized Patients with COVID-19-Preliminary Report RECOVERY Collaborative Group*.
      ]. Use of high doses of dexamethasone in early pregnancy has been associated with poor pregnancy outcomes in mice, mares, and dogs [
      • Solano M.E.
      • Arck P.C.
      Steroids, Pregnancy and Fetal Development.
      ]. These outcomes included early pregnancy termination, impaired fetal growth, and abnormal placentation [
      • Solano M.E.
      • Arck P.C.
      Steroids, Pregnancy and Fetal Development.
      ]. However, the RECOVERY trial utilized dexamethasone 6 mg daily, which is not high dose [
      • Horby P.
      • Lim W.S.
      • Emberson J.
      • et al.
      Dexamethasone for COVID-19-Preliminary Report Effect of Dexamethasone in Hospitalized Patients with COVID-19-Preliminary Report RECOVERY Collaborative Group*.
      ]. Data on the safety and efficacy of convalescent plasma in COVID-19 disease during pregnancy are emerging, and available data on the efficacy of this treatment in the general population currently demonstrate no difference in mortality [
      • Joyner M.J.
      • Bruno K.A.
      • Klassen S.A.
      • et al.
      Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients.
      ]. Two ongoing trials of convalescent plasma in pregnant patients with COVID-19 disease are ongoing (NCT04397757 and NCT04388527) [
      ,
      ]. Documented adverse effects of convalescent plasma use in the general population are rare but include febrile and allergic transfusion reactions, transfusion-related acute lung injury (TRALI), and anaphylaxis [
      • Piechotta V.
      • Chai K.L.
      • Valk S.J.
      • et al.
      Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.
      ]. Randomized trials of remdesivir use in COVID-19 have excluded pregnant and breastfeeding women, but the medication was used without documented harm in pregnant women during the Ebola and Marburg virus epidemics [
      • Mulangu S.
      • Dodd L.E.
      • Davey R.T.
      • et al.
      A randomized, controlled trial of Ebola virus disease therapeutics.
      ]. Remdesivir is available for the treatment of severe COVID-19 disease in pregnant women on a compassionate-use basis in the United States at the time of this article's production [
      • Igbinosa I.
      • Miller S.
      • Bianco K.
      • et al.
      Use of remdesivir for pregnant patients with severe novel coronavirus disease 2019.
      ]. Chloroquine/hydroxychloroquine, a popular treatment at the start of the pandemic, is not recommended for use in COVID-19 disease at the time of this review [
      • Huybrechts K.F.
      • Bateman B.T.
      • Zhu Y.
      • et al.
      Hydroxychloroquine early in pregnancy and risk of birth defects.
      ,
      • Lacroix I.
      • Bénévent J.
      • Damase-Michel C.
      Chloroquine and hydroxychloroquine during pregnancy: what do we know?.
      ]. Data from multiple trials have demonstrated no benefit with the use of chloroquine or hydroxychloroquine in COVID-19 [
      • Hussain N.
      • Chung E.
      • Heyl J.
      • et al.
      A Meta-Analysis on the Effects of Hydroxychloroquine on COVID-19.
      ]. Additionally, these medications are associated with maternal dysrhythmias, and hydroxychloroquine can cross the placenta and accumulate in fetal ocular tissue [
      • Louchet M.
      • Sibiude J.
      • Peytavin G.
      • Picone O.
      • Tréluyer J.-M.
      • Mandelbrot L.
      Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019.
      ,
      • Klinger G.
      • Morad Y.
      • Westall C.A.
      • et al.
      Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases.
      ,
      • Osadchy A.
      • Ratnapalan T.
      • Koren G.
      Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature.
      ]. Given the lack of documented benefit and the known risks of chloroquine/ hydroxychloroquine, they are not recommended for use in COVID-19. As pregnancy is a hypercoagulable state, thromboprophylaxis with low-molecular weight heparin in pregnant patients with COVID-19 should be considered, particularly those with elevated d-dimer levels [
      • Carlo Di Renzo G.
      • Giardina I.
      Coronavirus disease 2019 in pregnancy: Consider thromboembolic disorders and thromboprophylaxis.
      ]. The decision to start thromboprophylaxis should be made in conjunction with the patient and their obstetrician.

      3.6 Respiratory failure in pregnancy

      Respiratory failure can complicate the course of COVID-19 in pregnant patients. Emergency physicians should be cognizant of the impact of the anatomic and physiologic changes of pregnancy on intubation and mechanical ventilation (Table 3). Elevation of the diaphragm by the expanding uterus reduces functional residual capacity [
      • Schwaiberger D.
      • Karcz M.
      • Menk M.
      • Papadakos P.J.
      • Dantoni S.E.
      Respiratory failure and mechanical ventilation in the pregnant patient.
      ]. Oxygen consumption and carbon dioxide production are increased in pregnant patients due to the metabolic demands of the fetus [
      • Schwaiberger D.
      • Karcz M.
      • Menk M.
      • Papadakos P.J.
      • Dantoni S.E.
      Respiratory failure and mechanical ventilation in the pregnant patient.
      ]. This combination results in a shorter safe apnea time and faster desaturation following induction and paralysis. Pregnant patients are also at increased risk of aspiration secondary to a progesterone-mediated decrease in the tone of the lower esophageal sphincter, which can complicate intubation and positive-pressure ventilation in these patients [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. This is compounded by edema and hyperemia of the upper airways in pregnant patients, which increase the friability of the upper airways and decrease their caliber [
      • Lapinsky S.E.
      Management of Acute Respiratory Failure in pregnancy.
      ,
      • Lucarelli E.
      • Behn C.
      • Lashley S.
      • Smok D.
      • Benito C.
      • Oyelese Y.
      Mechanical ventilation in pregnancy due to COVID-19: a cohort of three cases.
      ]. Finally, increased progesterone levels result in increased tidal volume and minute ventilation in pregnant patients, inducing a state of respiratory alkalosis that promotes the transfer of oxygen from maternal circulation to the fetus [
      • Schwaiberger D.
      • Karcz M.
      • Menk M.
      • Papadakos P.J.
      • Dantoni S.E.
      Respiratory failure and mechanical ventilation in the pregnant patient.
      ,
      • Lapinsky S.E.
      Management of Acute Respiratory Failure in pregnancy.
      ,
      • Lucarelli E.
      • Behn C.
      • Lashley S.
      • Smok D.
      • Benito C.
      • Oyelese Y.
      Mechanical ventilation in pregnancy due to COVID-19: a cohort of three cases.
      ]. This should be considered when interpreting pre- and post-intubation blood gases, and every effort should be made to match the patient's pre-intubation minute ventilation once mechanical ventilation is initiated to avoid acidosis and fetal harm. While permissive hypercapnia and hypoxia have proven effective in the management of acute respiratory distress syndrome (ARDS) in the general population, it is uncertain how safe this strategy is in pregnant patients, who rely on maternal respiratory alkalosis for transplacental gas transfer to the fetus [
      • Schwaiberger D.
      • Karcz M.
      • Menk M.
      • Papadakos P.J.
      • Dantoni S.E.
      Respiratory failure and mechanical ventilation in the pregnant patient.
      ,
      • Lapinsky S.E.
      Management of Acute Respiratory Failure in pregnancy.
      ,
      • Lucarelli E.
      • Behn C.
      • Lashley S.
      • Smok D.
      • Benito C.
      • Oyelese Y.
      Mechanical ventilation in pregnancy due to COVID-19: a cohort of three cases.
      ]. Data on ECMO as a rescue therapy in pregnant patients with critical COVID-19 are limited, but it may be associated with favorable maternal and fetal outcomes in pregnant patients failing other therapies [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Fiore A.
      • Piscitelli M.
      • Adodo D.K.
      • et al.
      Successful use of extracorporeal membrane oxygenation postpartum as rescue therapy in a woman with COVID-19.
      ]. Because the success of ECMO as a salvage therapy is often dependent on its early use, consultation and potential transfer to an ECMO expert center should be considered in patients with critical disease failing conventional therapy [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ,
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ,
      • Fiore A.
      • Piscitelli M.
      • Adodo D.K.
      • et al.
      Successful use of extracorporeal membrane oxygenation postpartum as rescue therapy in a woman with COVID-19.
      ].
      Table 3The impact of anatomic and physiologic changes of pregnancy on respiratory failure and intubation
      Anatomic/ physiologic changeEffectPractical considerations
      Edema and hyperemia of the upper airwaysIncreased mucosal friability, decreased caliber of upper airwaysConsider using a smaller caliber endotracheal tube
      Decreased functional residual capacityShorter safe apnea timeExpect rapid desaturation; be prepared to intubate immediately after paralyzing
      Faster oxygen consumption
      Gravid abdomenAortocaval compression with prone positioningIf proning is necessary, offset the gravid uterus with pillows/blankets
      Increased tidal volume and minute ventilationPhysiologic respiratory alkalosisSet ventilator to match patient's pre-intubation minute ventilation
      Diminished lower esophageal sphincter toneIncreased aspiration riskAvoid bagging if possible
      Consider intubating in an upright position

      3.7 Disposition of COVID-19 pregnant patients and patient counseling

      Patients with mild disease and no co-morbidities can generally be discharged home with close return precautions, as approximately 3% will develop more severe disease (Fig. 1) [
      • Turan O.
      • Hakim A.
      • Dashraath P.
      • Jeslyn W.J.L.
      • Wright A.
      • Abdul-Kadir R.
      Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.
      ]. Consideration should be given to hospitalizing patients with mild disease complicated by one or more comorbidities, as these patients have a higher risk of decompensation and severe disease [
      • Salvatori G.
      • de Rose D.U.
      • Concato C.
      • et al.
      Managing COVID-19-positive maternal-infant dyads: an Italian experience.
      ]. Factors associated with more severe disease include obesity, hypertension, diabetes mellitus, maternal age greater than 40 years, and third-trimester pregnancy [
      • Salvatori G.
      • de Rose D.U.
      • Concato C.
      • et al.
      Managing COVID-19-positive maternal-infant dyads: an Italian experience.
      ].Those with severe or critical disease should be hospitalized, preferably at a center that has obstetrics services and an adult and neonatal ICU (Fig. 1) [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ].
      Fig. 1
      Fig. 1Algorithm for the disposition of pregnant patients with COVID-19.

      3.8 Breastfeeding

      Patients diagnosed with COVID-19 in late pregnancy or the puerperium may express concern about breastfeeding. Evidence regarding the transmission of SARS-CoV-2 in breastmilk is limited and therefore insufficient to make a recommendation for or against breastfeeding by COVID-19 infected mothers. Two studies looking at a total of 9 patients found no molecular evidence of the virus in breastmilk, whereas one study reported finding the virus in breastmilk more than one week after delivery [
      • Groß R.
      • Conzelmann C.
      • Müller J.A.
      • et al.
      Detection of SARS-CoV-2 in human breastmilk.
      ,
      • Gabriel M.Á.M.
      • Martínez A.M.M.
      • Martínez M.E.M.
      • Pedroche J.A.
      Negative transmission of SARS-CoV-2 to hand-expressed colostrum from SARS-CoV-2-positive mothers.
      ]. Given the paucity of evidence for transmission in breastmilk and the proven benefits of breastfeeding, the WHO and the Centers for Disease Control and Prevention recommend continued breastfeeding by mothers who are COVID-19 positive as long as basic hygiene measures are followed, including the wearing of a facemask by the mother during feeding [,
      ]. One study noted a decreased rate of breastfeeding in COVID-19 positive mothers, a factor previously documented to be associated with maternal-newborn separation at birth, which has been common in mothers positive for COVID-19 [
      • Gabriel Marín
      • Miguel A.
      • Mar Reyne Vergeli
      • Sonia Caserío Carbonero
      • Sole Laia
      • Tamara Carrizosa Molina
      • et al.
      Maternal, perinatal, and neonatal outcomes with COVID-19: a multicenter study of 242 pregnances and their 248 infant newborns during their first month of life.
      ].

      4. Conclusion

      COVID-19 is a potentially deadly infection, but data are limited concerning the pregnant population. Heterogeneity in study populations, testing protocols, and study results make it difficult to draw widespread conclusions, especially in studies with pregnant and puerperal individuals. Pregnant patients appear to present similarly to the general population, with fever and cough being the most reported symptoms in studies. Other than direct testing, no laboratory or imaging finding is sensitive or specific for the virus. Ground-glass opacities and bilateral infiltrates are the most commonly reported CT findings but are neither sensitive nor specific for COVID-19 infection. Lymphopenia has been commonly reported, as well as leukocytosis and leukopenia. Patients with mild disease and no co-morbidities can be safely discharged home. Close follow-up and return precautions should be provided, as 3% progress to severe or critical illness. Risk factors for death and severe disease include obesity, diabetes, and maternal age > 40 years. Women in their third trimester have the highest risk for critical illness, ICU admission, and need for mechanical ventilation. Evidence for transmission of SARS-CoV-19 through breastmilk is limited, and current guidelines recommend continued breastfeeding by COVID-19 positive mothers.

      Declaration of Competing Interest

      NONE for Dr. Boushra, Dr. Koyfman, and Dr. Long.

      Acknowledgements

      MB, BL, and AK conceived the idea for this manuscript and contributed substantially to the writing and editing of the review. This manuscript did not utilize any grants or funding, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

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