key: cord-1053037-llttu9nq authors: Syeda, Sbaa; Baptiste, Caitlin; Breslin, Noelle; Gyamfi-Bannerman, Cynthia; Miller, Russell title: The Clinical Course of COVID in Pregnancy date: 2020-07-21 journal: Semin Perinatol DOI: 10.1016/j.semperi.2020.151284 sha: 0a580342aafc12456ca2c5d0942845ad6e2ced8b doc_id: 1053037 cord_uid: llttu9nq The 2019 novel coronavirus disease (COVID-19) pandemic poses unique challenges to the medical community as the optimal treatment has not been determined and is often at the discretion of institutional guidelines. Pregnancy has previously been described as a high-risk state in the context of infectious diseases, given a particular susceptibility to pathogens and adverse outcomes. Although ongoing studies have provided insight on the course of this disease in the adult population, the implications of COVID-19 on pregnancy remains an understudied area. The objective of this study is to review the literature and describe clinical presentations among pregnant women afflicted with COVID-19. The 2019 novel coronavirus disease was first reported in the Hubei Province of Wuhan, China in December 2019. 1 Epidemiologic studies in early cases confirmed that the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly contagious and transmissible between humans. 2 Over the ensuing months, rapid increases in case numbers were observed worldwide, prompting the World Health Organization (WHO) to declare a pandemic on March 11, 2020. 3,4 With over 4 million cases confirmed and nearly 280,000 deaths globally, the COVID-19 pandemic continues to pose unique challenges to the medical community. 5 Importantly, because COVID-19 is an emerging infectious disease, the optimal treatment has not been determined and management is often based on individual institutional guidelines. 6 Pregnancy is generally regarded as a high-risk state in the context of infectious conditions, as the immunologic changes of pregnancy may increase susceptibility to pathogens and their associated complications. 7 Drawing from the experience of prior disease entities involving respiratory illnesses, there was an anticipation that pregnant women may not only experienced higher rates of complications but also could be at increased risk of mortality. [7] [8] [9] Although similar outcomes have not been confirmed in COVID-19, these historical lessons call for an immediate understanding of this disease in pregnancy, including clinical presentations, maternal and neonatal outcomes, and possible therapeutic interventions. Herein, we aim to review the published literature with a specific focus on clinical presentations among pregnant women afflicted with COVID-19. Disease surveillance, inclusive of both screening and diagnostic testing of various pathologic entities, is a fundamental public health tool required to mitigate disease dissemination. 10 While screening tools may help identify those at risk for a certain disease, diagnostic testing is often required for confirmation. Multiple strategies have been proposed for the screening and testing of COVID-19, as the understanding of the at-risk population evolved from recent travelers to asymptomatic community spread. As a result, the American College of Obstetricians and Gynecologists (ACOG) and Centers for Disease Control and Prevention (CDC) have developed guidelines to assist in triaging patients with suspected COVID-19. These statements encourage clinicians to prioritize testing in high risk populations while considering epidemiologic factors that may increase a patient"s a priori risk for the disease. 11 Furthermore, ACOG recognizes the potential for asymptomatic patients presenting to labor and delivery units and implores clinicians to consider additional strategies as appropriate. 12 Consistent with the guidance put forth by the CDC and ACOG, certain institutions based in geographic regions with higher COVID-19 disease prevalence have opted for universal testing of patients admitted to labor and delivery by via SARS-CoV-2 nasopharyngeal PCR. 13 At many New York City institutions, which are considered to be within an epicenter of the COVID-19 pandemic due to high case burden, implementation of universal testing via SARS-CoV-2 nasopharyngeal PCR has helped to provide a fuller understanding of the variable COVID-19 patient presentations that are possible among pregnant women. 14, 15 The various clinical characteristics of the COVID-19 infection have been documented in the literature as information continues to emerge. In large retrospective studies, common symptoms include the presence of fever, cough, myalgias, fatigue, and dyspnea. 16, 17 Less frequently, gastrointestinal symptoms such as nausea/vomiting and diarrhea may be exhibited. Neurological manifestations including anosmia, hypogeusia, and impaired consciousness have also been described. While this COVID-19 symptomatology may be similar in pregnant women, less is known about their clinical presentations, particularly as dyspnea, fatigue, nausea and vomiting are common pregnancy complaints. Therefore, we will review what is known for COVID-19 in the context of maternal adaptations to pregnancy and the physiologic changes that occur, in order to describe both the pulmonary and extrapulmonary manifestations of this disease entity. Included in the initial assessment and management of pregnant women with suspected or confirmed COVID-19 is the determination of illness severity. 12 In the largest cohort of over Among pregnant patients with significant symptoms, ACOG recommends prompt clinical evaluation for respiratory compromise with physical examination, blood gas analysis, pulse oximetry, and radiologic assessment as indicated. However, each of these objective measures may have varying results in the pregnant versus non-pregnant state. Understanding these differences is essential in order to identify patients at risk for worsening disease. Perhaps the most striking change in respiratory physiology during pregnancy is an increase in resting minute ventilation, which is driven primarily by an increase in tidal volume while maternal respiratory rate remains nearly unchanged. 23 In comparison to non-pregnant adults, this relative hyperventilation causes arterial pCO2 to decline with a compensatory decrease in serum bicarbonate. There is additionally a rise in arterial pO2. This compensated respiratory alkalosis defines the normal acid-base status of pregnancy and is integral in the evaluation of critical patients. In pregnant patients with COVID-19 infections, defining indications for oxygen supplementation requires attention to both maternal and fetal status. In addition to standard criteria for oxygen supplementation, the WHO recommends a higher oxygenation goal in pregnancy, for fetal benefit. In a stable patient undergoing resuscitation, target SpO 2 goal is >90% in a non-pregnant adult, while this goal increases to >92-95% in pregnant women. 24 Furthermore, while permissive hypercapnia in acute respiratory failure may allow for protective ventilation, maternal hypercapnia may cause fetal respiratory acidosis and is thus may not be a desirable option in the management of pregnant women. 25 While identification of patients requiring supplemental oxygenation is easily achievable in the inpatient setting, a recent report of patients with "silent hypoxia" has been described, wherein patients without respiratory distress have low SpO 2 levels. Though clinically well appearing, these patients have the propensity to deteriorate quickly. 26 Many studies have cited the role of laboratory investigations in the identification of patients at risk for severe or critical disease. 17, 30, 31 Importantly, the pathophysiology of COVID-19 infection appears to involve a pro-inflammatory and prothrombotic state. 32 Interpretation of common markers of inflammation and thrombosis, however, may be limited in pregnancy given a known baseline elevation in serum reactants during this time. An understanding of the normal hematologic and immunologic parameters in pregnancy is necessary in the interpretation of COVID-19 severity. A commonly cited laboratory finding among patients with COVID-19 is a normal white blood cell count accompanied by a depressed total lymphocyte count, or lymphopenia. Pregnancy, on the other hand, is characterized by a physiologic mild leukocytosis with neutrophilia. 33 In a retrospective review of 55 pregnant women, a lower lymphocyte count was noted in patients with confirmed COVID-19 in comparison to controls, which may indicate that lymphopenia is a reliable marker for disease progression in this population. 34 In The complex interplay between the immune response to infection and the activation of coagulation pathways results in a procoagulant state in patients afflicted by Patients are at risk for both arterial and venous thrombi, leading the WHO to release interim guidance for the use of prophylactic heparin among these patients. 11,36 Pregnancy also poses an increased risk of hypercoagulability. 37 As a result, use of venous thromboembolism prophylaxis among pregnant and postpartum patients with COVID-19 is also recommended. 21 Increased maternal and fetal metabolic demands throughout pregnancy give rise to hemodynamic changes during this time. 38 Knowledge of these physiologic responses, including an increased cardiac output, expanded plasma volume, and reduced vascular resistance, are required to interpret cardiovascular tests in pregnancy and guide treatment. 39 With regards to COVID-19 in the general adult population, the cardiovascular complications include direct myocardial injury/myocarditis, cardiomyopathy, myocardial infarction, and arrhythmia. 40 Select case reports have documented cardiovascular findings in the obstetric population, including COVID-19 related cardiomyopathy. 41 Additionally, several studies in the non-pregnant population have shown that pre-existing cardiovascular disease or development of cardiac injury may predispose patients to significantly worse outcome. 40, 42 Although no specific studies have assessed this association in pregnancy, pregnant women with underlying cardiovascular or metabolic disease may be at elevated risk for complications related to COVID-V. Liver injury may be present among COVID-19 patients at nearly all spectrums of the disease. 43 Recent studies in non-obstetric populations have documented the incidence of hepatic involvement ranges from 14.8% to 53%, as demonstrated by elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. 44 In a study assessing non-ICU hospitalized adults, nearly one-third of patients had serologic evidence of liver injury. 43 Although the specific cause for these abnormalities is unclear, elevations in serum biochemistries may ultimately reflect direct virus-induced cytotoxic effect or immune-mediated inflammation. 45 The neurologic manifestations of COVID-19 have been described in three different categories: central nervous system manifestations, peripheral nervous system manifestations, and skeletal muscular injury manifestations. 49 prompt an investigation for pre-eclampsia in the obstetric population. Akin to the hepatic manifestations of this disease, the exact etiology of acute kidney injury (AKI) among patients with COVID-19 is unclear. While some studies have purported AKI is secondary to multi-organ failure and shock, others have suggested the possibility of direct virus-induced cytotoxic effect. 50, 51 With the normal progression of pregnancy, both plasma and interstitial oncotic pressure fall, with the latter decreasing to a greater extent. Therefore, special precaution should be taken with fluid resuscitation among pregnant patients. There is additionally an increase in capillary hydrostatic pressure. 52 The combination of these two forces results in extravasation of fluids into the interstitial space in pregnancy. As a result, pregnant patients with AKI and pulmonary injury secondary to SARS-CoV-2 may be at particular risk for pulmonary edema. Serial volume assessments in the context of the specific clinical scenario must be undertaken to determine the appropriate fluid resuscitation goals for each individual patient. Management of AKI typically begins with conservative efforts, with close attention to potential electrolyte derangements and fluid status of the patient as the disease progresses. Discontinuation or judicious use of nephrotoxic medications are necessary management strategies in caring for women with COVID-19 infection. Renal replacement therapy is reserved for kidney injury not responsive to supportive management. In the pregnant patient, similar principles are applicable in the management of AKI; however, additional obstetric etiologies of AKI such as severe preeclampsia must be taken into consideration. COVID-19 infection results in both pulmonary and extra-pulmonary manifestations. While the multi-organ involvement of this disease entity has been cited extensively in the literature, there is limited data confirming these findings in the obstetric population. Herein, we reviewed the presentation of this disease per organ system, as well as special considerations that must be undertaken among pregnant patients. Future studies assessing specific findings in the obstetric population will allow clinicians to gain a better understanding of the progression of this disease and develop guidelines for system-based treatment as this pandemic continues to unfold. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China The First 75 Days of Novel Coronavirus Outbreak: Recent Advances, Prevention, and Treatment World Health Organization, World Health Organization, www.who.int/news-room/detail/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations WHO Director-General's Opening Remarks at the Media Briefing on World Health Organization, World Health Organization, www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefingon-covid An interactive web-based dashboard to track COVID-19 in real time Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records H1N1 2009 influenza virus infection during pregnancy in the USA Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome Reducing the Odds: Preventing Perinatal Transmission of HIV In The United States Interim Guidance: Healthcare Professionals 2019-NCoV pregnancy: early lessons COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals Universal Screening for SARS-CoV-2 in Women Admitted for Delivery COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020. 19 Novel corona virus disease (COVID-19) in pregnancy: What clinical recommendations to follow? Management Considerations for Pregnant Patients With COVID-19. Society for Maternal and Fetal Medicine Universal Screening for SARS-CoV-2 in Women Admitted for Delivery: NEJM Clinical Management of Severe Acute Respiratory Infection When COVID-19 Is World Health Organization, World Health Organization, www.who.int/publicationsdetail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected Implications for the pregnant patient The mystery of the pandemic's 'happy hypoxia Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED's Experience during the COVID-19 Pandemic ACR Recommendations for the Use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection A Review of Coronavirus Disease-2019 (COVID-19) Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China COVID-19 cytokine storm: the interplay between inflammation and coagulation Disseminated Intravascular Coagulation Clinical features and outcomes of pregnant women suspected of coronavirus disease 2019 Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up Pregnancy and thrombotic risk Hemodynamic changes in pregnancy Pregnancy: a stress test for life Cardiovascular complications in COVID Two cases of coronavirus 2019-related cardiomyopathy in pregnancy Cardiovascular disease and COVID-19 Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: A retrospective study Liver injury during highly pathogenic human coronavirus infections Hepatic and gastrointestinal involvement in coronavirus disease 2019 (COVID-19): What do we know till now? Liver injury in COVID-19: management and challenges COVID-19 Resources: AASLD COVID-19 | SMFM.org -The Society for Maternal-Fetal Medicine Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease The Novel Coronavirus 2019 epidemic and kidneys Fluid Management in the Complicated Obstetric Patient The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.