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SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review

      Abstract

      The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities. Data from previous pandemics and seasonal influenza suggest that pregnant women may be at increased risk for infection-associated morbidity and mortality. Physiologic changes in normal pregnancy and metabolic and vascular changes in high-risk pregnancies may affect the pathogenesis or exacerbate the clinical presentation of COVID-19. Specifically, SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) receptor, which is upregulated in normal pregnancy. Upregulation of ACE2 mediates conversion of angiotensin II (vasoconstrictor) to angiotensin-(1-7) (vasodilator) and contributes to relatively low blood pressures, despite upregulation of other components of the renin-angiotensin-aldosterone system. As a result of higher ACE2 expression, pregnant women may be at elevated risk for complications from SARS-CoV-2 infection. Upon binding to ACE2, SARS-CoV-2 causes its downregulation, thus lowering angiotensin-(1-7) levels, which can mimic/worsen the vasoconstriction, inflammation, and pro-coagulopathic effects that occur in preeclampsia. Indeed, early reports suggest that, among other adverse outcomes, preeclampsia may be more common in pregnant women with COVID-19. Medical therapy, during pregnancy and breastfeeding, relies on medications with proven safety, but safety data are often missing for medications in the early stages of clinical trials. We summarize guidelines for medical/obstetric care and outline future directions for optimization of treatment and preventive strategies for pregnant patients with COVID-19 with the understanding that relevant data are limited and rapidly changing.

      Abbreviations and Acronyms:

      ACE2 (angiotensin-converting enzyme 2), ACOG (American College of Obstetricians and Gynecologists), Ang (angiotensin), ARDS (acute respiratory distress syndrome), CD (cesarean delivery), CDC (Centers for Disease Control and Prevention), CL (cervical length), COVID-19 (coronavirus disease 2019), CRP (C-reactive protein), CT (computed tomography), CVS (chorionic villus sampling), F2F (face to face), FDA (Food and Drug Administration), F/U (follow-up), GA (general anesthesia), GBS (group B streptococcus), HCQ (hydroxychloroquine), HCW (health care worker), HIV (human immunodeficiency virus), ICU (intensive care unit), IL (interleukin), IOL (induction of labor), ISUOG (International Society of Ultrasound in Obstetrics and Gynecology), NAFTNet (North American Fetal Therapy Network), NSAID (nonsteroidal anti-inflammatory drug), NST (nonstress test), PPE (personal protective equipment), qRT-PCR (quantitative reverse transcriptase polymerase chain reaction), RAAS (renin-angiotensin-aldosterone system), RCOG (Royal College of Obstetricians and Gynaecologists), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), SMFM (Society for Maternal-Fetal Medicine), TMPRSS2 (transmembrane serine protease 2), US (ultrasonography), VD (vaginal delivery), WHO (World Health Organization)
      Article Highlights
      • Physiologic, metabolic, and vascular changes in normal and high-risk pregnancies may affect risks for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and modify/exacerbate the clinical presentation of coronavirus disease 2019 (COVID-19).
      • Pregnant women may be at greater risk for SARS-CoV-2 infection, with more severe COVID-19 symptoms and worse pregnancy outcomes.
      • Studies to date have reported higher risks of pregnancy complications, including preterm birth and preeclampsia, as well as higher rates of cesarean delivery.
      • Pharmacologic therapy is limited to medications with proven safety during pregnancy and lactation; safety data are often unavailable for medications in the early stages of clinical trials.
      • The current recommendations are based on a limited number of studies. Future large, likely multicenter, studies will be critical in improving our understanding of the pathophysiology and clinical characteristics of COVID-19 and pregnancy, which may optimize COVID-19 preventive and treatment strategies during normal and high-risk pregnancies.
      Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses characterized by spherical morphologic features with surface spike projections. Human coronaviruses are divided into alphacoronaviruses and betacoronaviruses. The rapid emergence and human-to-human transmission of a virulent novel lineage B betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in the global pandemic of coronavirus disease 2019 (COVID-19) associated with considerable morbidity and mortality.
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      Worldwide population studies to date have identified several patient characteristics, including age and comorbid conditions, as risk factors for poor outcomes, but data on pregnant patients are limited. Based on data from previous pandemics, pregnant women
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      are at higher risk for acquiring infection and dying compared with nonpregnant women. The current review provides a multidisciplinary summary of the course and management of COVID-19 during pregnancy using an evidence base that has been published since identification of the first patients in Wuhan, China, in December 2019.

      Taxonomy and Phylogeny of Select Human Coronaviruses

      Virion and Viral Life Cycle

      The capsid of SARS-CoV-2 contains an RNA genome complexed with a nucleocapsid protein. The membrane surrounding this nucleocapsid contains 3 proteins common to all coronaviruses: spike protein, membrane protein M, and small membrane protein E (Figure 1A).
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      Viral entry occurs via 2 routes. The first occurs when the spike protein attaches to the angiotensin-converting enzyme 2 (ACE2) receptor, releasing the viral genome and nucleocapsid protein into the host cell cytoplasm.
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      Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus.
      The other pathway is the direct plasma membrane route via transmembrane serine protease 2 (TMPRSS2), which allows for proteolytic cleavage of the spike protein and mediation of fusion with the cell membrane.
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      The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade.
      Intracellularly, the viral genome is translated into a replicase to produce more genome RNA, messenger RNA, and viral protein. Viral membrane proteins M, N, and E assemble on intracellular membranes. The nucleocapsid protein and viral RNA complex form a helical capsid structure, which buds between the endoplasmic reticulum and the Golgi apparatus. Mature viral particles are packaged in vesicles, transported to the cell membrane, and released from the cell (Figure 1B).
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      Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus.
      Figure thumbnail gr1
      Figure 1Features and life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A, Structure of the SARS-CoV-2 viron. B, Viral entry methods and replication of SARS-CoV-2.

      Viral Tropism and Normal and High-Risk Pregnancies

      The ACE2 enzyme plays a key role in the conversion of angiotensin Ang I to Ang-(1-9) and Ang II to Ang-(1-7) (vasodilatory, antithrombotic, and anti-inflammatory activities) (Figure 2). The hormonal profile of normal gestation is characterized by an early increase of all the components of the renin-angiotensin-aldosterone system (RAAS), including ACE2.
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      Enhanced expression of Ang-(1-7) during pregnancy.
      This raises the possibility that pregnant women may be at a greater risk for SARS-CoV-2 infection. In addition, low blood pressure in pregnant women is maintained through a balance between being refractory to the pressor effects of Ang II and increased levels of Ang-(1-7), which exhibit systemic vasodilatory responses.
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      Angiotensin-(1-7) in normal and preeclamptic pregnancy.
      In preeclampsia, a pregnancy-specific hypertensive disorder that affects 3.5% of all pregnancies
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      Incidence and long-term outcomes of hypertensive disorders of pregnancy.
      clinically is characterized by multisystem involvement and, commonly, proteinuria; this balance is lost, with an overexaggerated Ang II blood pressure response.
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      Causes and consequences of the dysregulated maternal renin-angiotensin system in preeclampsia.
      Preeclampsia has also been associated with decreased maternal plasma Ang-(1-7) levels.
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      • Ferrario C.M.
      • Brosnihan K.B.
      Angiotensin-(1-7) in normal and preeclamptic pregnancy.
      Because SARS-CoV-2 not only binds to ACE2 but also causes its downregulation,
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      Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63.
      infections during pregnancy may potentiate the RAAS abnormalities, ie, increased Ang II relative to decreased Ang-(1-7), that are present in preeclampsia. COVID-19 and preeclampsia share additional common mechanisms, including endothelial cell dysfunction and coagulation abnormalities. Notably, ACE2 receptors are also expressed by endothelial cells,
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      Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function.
      and endothelial cell infection and immune cell–mediated endothelial injury have been recently described in COVID-19.
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      Endothelial cell infection and endotheliitis in COVID-19.
      Because the hallmark of preeclampsia is endothelial dysfunction,
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      Hypertension in pregnancy: an emerging risk factor for cardiovascular disease.
      infection with SARS-CoV-2 during pregnancy could mimic and/or initiate microvascular dysfunction by causing endotheliitis. Systemic inflammation and microcirculatory dysfunction, characterized by vasoconstriction and resultant ischemia, ensue. This can further contribute to a pro-coagulopathic state, as demonstrated by high rates of deep vein thrombosis, stroke, and pulmonary embolism, which are increasingly reported in patients with COVID-19.
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      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China [published online April 10, 2020].
      Infection with SARS-CoV-2 during pregnancy can be particularly prothrombotic because coagulation abnormalities may potentiate a hypercoagulable state, which is already present in uncomplicated pregnancy and exacerbated by preeclampsia.
      • Garovic V.D.
      • Hayman S.R.
      Hypertension in pregnancy: an emerging risk factor for cardiovascular disease.
      Similarly, complement activation, which is present in both preeclampsia
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      • Willrich M.A.V.
      The complement alternative pathway and preeclampsia.
      and COVID-19,
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      • et al.
      Complement as a target in COVID-19 [published online April 23, 2020]?.
      may result in particularly severe thrombotic vascular injury when these disease states are present concurrently. In summary, RAAS abnormalities, endothelial dysfunction, complement activation, and the pro-coagulopathic effects of COVID-19 are similar to those occurring in preeclamptic pregnancies, potentially resulting in progressive vascular damage. Therefore, pregnancy and its complications represent a vulnerable state for invasive infection with SARS-CoV-2, reflecting several overlapping cellular mechanisms.
      Figure thumbnail gr2
      Figure 2Pregnancy, coronavirus disease 2019 (COVID-19), and mechanisms of vascular damage. Upregulation of angiotensin-converting enzyme 2 (ACE2) receptor in pregnancy may increase the risk of severe acute respiratory syndrome coronavirus 2 infection. Binding of virus to ACE2 causes its downregulation and may increase angiotensin (Ang) II relative to Ang-(1-7), thus favoring vasoconstriction, which can mimic/worsen vascular dysfunction in preeclampsia.
      In addition to the direct cytotoxic effect of the virus, tissue injury in COVID-19 is mediated through an excessive inflammatory response, commonly referred to as cytokine storm. Cytokine storm is mediated via immune responses, which are significantly modified in pregnancy, and may contribute to COVID-19 laboratory and clinical characteristics during pregnancy.

      Immune Responses to COVID-19

      During pregnancy, the maternal immune system must adjust to tolerate the semiallogeneic fetus while maintaining its ability to respond to pathogenic insult.
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      Fetal sex-based differences in maternal hormones, angiogenic factors, and immune mediators during pregnancy and the postpartum period.
      This is also known as T helper 2 polarization. However, near the end of pregnancy a switch to T helper 1 immunity occurs and the maternal immune system becomes proinflammatory, leading to the sequence of events that occur before parturition (ie, cervical dilation, contractions). Data on immune responses to SARS-CoV-2 in pregnant women are lacking at this time, and data from previous pandemics, suggest that pregnancy may increase the risk of acquiring infection and dying compared with nonpregnant women.
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      Pandemic Influenza and Pregnancy Working Group. Pandemic influenza and pregnant women: summary of a meeting of experts.
      The timing of infection during gestation may induce differences in maternal immune responses, viral clearance, and, ultimately, perinatal outcomes. Because the first and third trimesters are proinflammatory to promote implantation and labor,
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      • Aldo P.
      • Alvero A.B.
      The unique immunological and microbial aspects of pregnancy.
      pregnant women infected with SARS-CoV-2 during these trimesters may be at higher risk for exaggerated responses to virus (cytokine storm). Furthermore, high levels of stress and inflammation occur during labor, and the physiologic changes that occur in a mother’s body after the baby is born could lead to poor maternal COVID-19 outcomes postpartum. This has been observed clinically, where pregnant women with mild symptoms on admission to the hospital for delivery required postpartum hospital admission for respiratory symptoms.
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      COVID-19 in pregnancy: early lessons.
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      COVID-19 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals [published online April 9, 2020].
      Conflicting data exist regarding vertical transmission of the virus; however, research on other coronavirus infections during pregnancy suggests that in utero transmission does not occur. Mouse models and epidemiologic data have shown that inflammatory immune responses generated by viral infection during pregnancy can result in negative effects on fetal brain development.
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      During the H1N1 pandemic, infected women had higher rates of preterm birth.
      • Siston A.M.
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      Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.
      Therefore, although placental transmission of the virus may not occur with SARS-CoV-2 infection, other short- and long-term effects from inflammation may adversely affect the developing fetus. These require further characterization. Maternal immunity may be passed on to protect the fetus, conferring passive immunity. Immunoglobulin G specific to the 2003 SARS-CoV outbreak strain was found not only in maternal blood, but also in amniotic fluid and cord blood.
      • Jiang X.
      • Gao X.
      • Zheng H.
      • et al.
      Specific immunoglobulin G antibody detected in umbilical blood and amniotic fluid from a pregnant woman infected by the coronavirus associated with severe acute respiratory syndrome.
      Another possible source of antibodies could be breast milk, but this has yet to be determined.

      Maternal Physiology and Clinical Characteristics of COVID-19 During Pregnancy

      Significant physiologic changes to respiration occur during pregnancy,
      • Hegewald M.J.
      • Crapo R.O.
      Respiratory physiology in pregnancy.
      including increased secretions and congestion in the upper airways, increased chest wall circumference, and upward displacement of the diaphragm. These changes result in decreased residual volume and increased tidal volume and air trapping, slightly decreased airway resistance, stable diffusion capacity, increased minute ventilation, and increased chemosensitivity to carbon dioxide. Hemodynamic changes include increased plasma volume of 20% to 50%, increased cardiac output, and decreased vascular resistance.
      • Hegewald M.J.
      • Crapo R.O.
      Respiratory physiology in pregnancy.
      These changes result in a state of physiologic dyspnea and respiratory alkalosis as well as an increased susceptibility to respiratory pathogens. As has been seen with other viral respiratory infections, the early symptoms of SARS-CoV-2 infection may mimic physiologic dyspnea in pregnancy, which could result in delayed diagnosis and more severe disease.
      Society for Maternal-Fetal Medicine
      Management considerations for pregnant patients with COVID-19 developed with guidance from Torre Halscott, MD, MS and Jason Vaught, MD.
      Pregnant women with SARS-CoV-2 infection may experience more severe symptoms compared with nonpregnant women. Existing limited data have reported on rapid deterioration in women who had no symptoms on arrival and were subsequently diagnosed as having severe COVID-19.
      • Breslin N.
      • Baptiste C.
      • Miller R.
      • et al.
      COVID-19 in pregnancy: early lessons.
      In some, but not all, patients, maternal comorbidities were present (hypertension, diabetes, cholestasis of pregnancy).
      • Breslin N.
      • Baptiste C.
      • Miller R.
      • et al.
      COVID-19 in pregnancy: early lessons.
      ,
      • 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 [published online March 17, 2020].
      Case reports have also described cases of quickly worsening maternal status with the ultimate diagnosis of cardiomyopathy.
      • Juusela A.
      • Nazir M.
      • Gimovsky M.
      Two cases of coronavirus 2019–related cardiomyopathy in pregnancy [published online April 3, 2020].
      Unfortunately, these rapidly progressive maternal complications have led to a high rate of cesarean deliveries (CDs) for either worsening maternal status or nonreassuring fetal status secondary to the worsening maternal clinical state.
      Preeclampsia is an example of a common pregnancy-related complication that may be exacerbated by, or may exacerbate, COVID-19, as previously discussed. The picture becomes further complicated because the two processes share common laboratory abnormalities. Thus, it may be difficult to discern whether certain abnormal laboratory findings are due to SARS-CoV-2 infection or preeclampsia, and this interplay may have treatment implications. For example, thrombocytopenia
      • Lippi G.
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      • Henry B.M.
      Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis.
      and liver function abnormalities,
      • Zhang C.
      • Shi L.
      • Wang F.S.
      Liver injury in COVID-19: management and challenges.
      both of which are diagnostic criteria for preeclampsia with severe features, are also associated with worsening COVID-19.

      Maternal Disease and Outcomes

      Physiologic changes in normal pregnancy and metabolic and vascular changes in high-risk pregnancies may affect the pathogenesis or exacerbate the clinical presentation of COVID-19 during pregnancy. A systematic review by Di Mascio et al
      • Di Mascio D.
      • Khalil A.
      • Saccone G.
      • et al.
      Outcome of coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis [published online March 25, 2020].
      evaluating and comparing obstetric outcomes in combined coronavirus infections (SARS, Middle East respiratory syndrome, and SARS-CoV-2) found that SARS-CoV-2 alone resulted in higher rates of preterm birth (24.3% [95% CI, 12.5% to 38.6%] for <37 weeks’ gestation and 21.8% [95% CI, 12.5% to 32.9%] for <34 weeks’ gestation), preeclampsia (16.2% [95% CI, 4.2% to 34.1%]), and CD (83.9% [95% CI, 73.8% to 91.9%]).
      As of April 22, 2020, a total of 23 studies
      • Breslin N.
      • Baptiste C.
      • Gyamfi-Bannerman C.
      • et al.
      COVID-19 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals [published online April 9, 2020].
      ,
      • Juusela A.
      • Nazir M.
      • Gimovsky M.
      Two cases of coronavirus 2019–related cardiomyopathy in pregnancy [published online April 3, 2020].
      ,
      • Zhu H.
      • Wang L.
      • Fang C.
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      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      • Wang X.
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      • Zhu F.
      • Tang Y.
      • Shen X.
      A case of 2019 novel coronavirus in a pregnant woman with preterm delivery [published online March 25, 2020].
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      • Huang B.
      • Luo D.J.
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      Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases [in Chinese].
      • Liu Y.
      • Chen H.
      • Tang K.
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      Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy [published online March 4, 2020].
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      • Zhao R.
      • Zheng S.
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      Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China.
      • Chen H.
      • Guo J.
      • Wang C.
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      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
      • Zhang L.
      • Jiang Y.
      • Wei M.
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      Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province [in Chinese].
      • Liu D.
      • Li L.
      • Wu X.
      • et al.
      Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis [published online March 18, 2020].
      • Wen R.
      • Sun Y.
      • Xing Q.-S.
      A patient with SARS-CoV-2 infection during pregnancy in Qingdao, China [published online March 10, 2020].
      • Li N.
      • Han L.
      • Peng M.
      • et al.
      Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study [published online March 30, 2020].
      • Yu N.
      • Li W.
      • Kang Q.
      • et al.
      Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study.
      • Xia H.
      • Zhao S.
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      • Luo H.
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      Emergency Caesarean delivery in a patient with confirmed COVID-19 under spinal anaesthesia.
      • Chen R.
      • Zhang Y.
      • Huang L.
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      Safety and efficacy of different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a case series of 17 patients.
      • Dong L.
      • Tian J.
      • He S.
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      • Zambrano L.I.
      • Fuentes-Barahona I.C.
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      A pregnant woman with COVID-19 in Central America [published online March 25, 2020].
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      • Sun R.
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      • Zhang S.
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      Radiological findings and clinical characteristics of pregnant women with COVID-19 pneumonia [published April 8, 2020].
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      Vaginal delivery report of a healthy neonate born to a convalescent mother with COVID-19 [published online April 10, 2020].
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      (excluding overlapping of case reports) addressing obstetrical and neonatal outcomes of SARS-CoV-2 infection in pregnancy have been published in English. These studies span January 1, 2020, to April 22, 2020, and include 185 patients. The abstracted information is presented in Table 1, which summarizes maternal and neonatal outcomes. Briefly, most of the diagnoses occurred in the third trimester. Fever was the most common presenting symptom, followed by cough, dyspnea, and gastrointestinal alterations. Slightly more than 25% of patients were asymptomatic at diagnosis. The most common laboratory findings were lymphopenia and neutrophilia. Pneumonia was a common diagnosis (40%), and a small percentage (3.24%) required intensive care unit admission.
      Table 1Summary of Maternal and Neonatal Outcomes During the COVID-19 Pandemic
      COVID-19 = coronavirus disease 2019; CT = computed tomography; ICU = intensive care unit; qRT-PCR = quantitative reverse transcriptase polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
      Note that certain parameters were not evaluated or reported in all patients, so the denominators used for calculations represent only the numbers for which data are available.
      CharacteristicValue (N=185)
      Maternal data
      Age (y), mean (range)29.6 (20-41)
      Trimester (No./total No. [%])
       First3/185 (1.62)
       Second5/185 (2.70)
       Third177/185 (95.68)
      Signs and symptoms (No./total No. [%])
       Fever90/169 (53.25)
       Pneumonia75/184 (40.76)
       Cough56/169 (33.13)
       Asymptomatic44/169 (26.03)
       Dyspnea/shortness of breath22/169 (13.01)
       Gastrointestinal alterations9/169 (5.32)
       ICU admission6/185 (3.24)
      Diagnostic method (No./total No. [%])
       qRT-PCR SARS-CoV-2 only179/185 (96.75)
       CT changes only6/185 (3.24)
       qRT-PCR SARS-CoV-2 and CT changes100/185 (54.05)
      Laboratory alterations
       Lymphopenia32/93 (34.40)
       Neutrophilia8/93 (8.60)
      Interventions (No./total No. [%])
       Antibiotics64/145 (44.13)
       Supportive measures41/145 (28.27)
       Antiviral therapy39/145 (26.90)
       Corticosteroids12/145 (8.28)
      Obstetric comorbidities (No./total No. [%])
      Thirty-three of 185 patients (17.8%) were still pregnant at the end of this study; therefore, rates of complications occurring in late pregnancy or close to delivery, such as preeclampsia, might have been underestimated.
       Gestational hypertension6/182 (3.29)
       Preeclampsia4/182 (2.20)
       Gestational diabetes11/182 (6.04)
       Prelabor rupture of membranes13/184 (7.07)
       Fetal distress23/184 (12.50)
      Patient status (No./total No. [%])
       Delivered152/185 (82.16)
       Still pregnant33/185 (17.83)
      Mode of delivery (No./total No. [%])
       Cesarean delivery129/152 (84.86)
       Vaginal delivery19/152 (12.50)
       Pregnancy termination4/152 (2.63)
      Gestational age at delivery of viable pregnancies (No./total No. [%])
       <28 wk0/148 (0.00)
       28-31 6/7 wk2/148 (1.35)
       32-35 6/7 wk26/148 (17.56)
       ≥36 wk96/148 (64.86)
       Missing data24/148 (16.21)
      Neonatal data
      Neonates reported (No./total No. [%])
       Total146 (100)
      Live births145/146 (99.31)
      Stillbirths1/146 (0.68)
      Comorbidities after live birth (No./total No. [%])
      Neonatal ICU admission27/145 (18.62)
      Low birth weight15/145 (10.34)
      Pneumonia9/145 (6.20)
      qRT-PCR SARS-CoV-2 positive2/145 (1.37)
      Neonatal death1/145 (0.69)
      a COVID-19 = coronavirus disease 2019; CT = computed tomography; ICU = intensive care unit; qRT-PCR = quantitative reverse transcriptase polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
      b Note that certain parameters were not evaluated or reported in all patients, so the denominators used for calculations represent only the numbers for which data are available.
      c Thirty-three of 185 patients (17.8%) were still pregnant at the end of this study; therefore, rates of complications occurring in late pregnancy or close to delivery, such as preeclampsia, might have been underestimated.
      Management of patients varied according to institution. Most were treated with medications that are considered to be relatively safe during pregnancy: antibiotics (cefoperazone, sulbactam, ceftriaxone, cefazolin, and azithromycin), antiviral therapy (lopinavir, ritonavir, oseltamivir, and ganciclovir), and a few were treated with corticosteroids (dexamethasone, methylprednisolone).
      Due to the high false-negative rates of the nasopharyngeal swab for the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for the SARS-CoV-2 test,
      • Kelly J.C.
      • Dombrowksi M.
      • O’Neil-Callahan M.
      • Kernberg A.S.
      • Frolova A.I.
      • Stout M.J.
      false-negative COVID-19 testing: considerations in obstetrical care [published online April 28, 2020].
      computed tomography may be required to confirm the diagnosis in cases of high suspicion, as seen in 4 cases reported by Wu et al.
      • Wu X.
      • Sun R.
      • Chen J.
      • Xie Y.
      • Zhang S.
      • Wang X.
      Radiological findings and clinical characteristics of pregnant women with COVID-19 pneumonia [published April 8, 2020].
      There were no patients who delivered before 28 weeks’ gestation, and most patients delivered at 36 0/7 weeks or later. The impact of infection on timing of delivery is still unclear. Liu et al
      • Liu Y.
      • Chen H.
      • Tang K.
      • Guo Y.
      Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy [published online March 4, 2020].
      reported a 46% preterm labor rate between 32 and 36 weeks of gestation in 10 patients admitted with positive SARS-CoV-2 infection, and Zhang et al
      • Zhang L.
      • Jiang Y.
      • Wei M.
      • et al.
      Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province [in Chinese].
      reported no difference in mean ± SD gestational age at delivery for 16 women with SARS-CoV-2 infection (38.7±1.4 weeks) and 45 women without SARS-CoV-2 infection (37.9±1.6 weeks).
      A systematic review by Zaigham and Andersson
      • Zaigham M.
      • Andersson O.
      Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies [published online April 7, 2020].
      including 108 pregnant women reported that CD was the most common mode of delivery, with a rate of 92%. It can be speculated that SARS-CoV-2 infections are more likely to result in maternal hypoxia or increased oxygen requirements, resulting in a nonreassuring fetal heart tracing, warranting expedited delivery. There may also be lack of SARS-CoV-2 screening in some health care settings, resulting in selection bias for CD in severe cases. The indication for CD needs to be further evaluated because current guidelines indicate that SARS-CoV-2 infection alone is not an indication for CD.
      Royal College of Obstetricians and Gynaecologists
      Coronavirus (COVID-19) infection in pregnancy: information for healthcare professionals.
      ,
      • Boelig R.C.
      • Saccone G.
      • Bellussi F.
      • Berghella V.
      MFM Guidance for COVID-19 [published online March 19, 2020].
      A recent multicenter cohort study of severe COVID-19 in pregnant patients from 12 US institutions reported that patients were usually admitted to the hospital with severe disease 7 days after the onset of symptoms and typically were intubated 2 days after admission.
      • Pierce-Williams R.A.M.
      • Burd J.
      • Felder L.
      • et al.
      Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study [published online May 8, 2020].
      Fifty percent of women required delivery, resulting in a high rate of preterm birth.

      Neonatal Outcomes

      Neonatal outcomes are shown in Table 1. There was 1 reported stillbirth
      • Liu Y.
      • Chen H.
      • Tang K.
      • Guo Y.
      Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy [published online March 4, 2020].
      (<1%) due to severe maternal disease with multiple organ failure and 1 neonatal death
      • Zhu H.
      • Wang L.
      • Fang C.
      • et al.
      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      (<1%) due to refractory shock with multiple organ failure after delivery at 34 5/7 weeks’ gestation. Among the 145 live births, 2 neonates tested positive for SARS-CoV-2 infection. Both did well with supportive therapy and observation and were discharged from the hospital in stable condition.
      • Yu N.
      • Li W.
      • Kang Q.
      • et al.
      Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study.
      ,
      • Zamaniyan M.
      • Ebadi A.
      • Aghajanpoor Mir S.
      • Rahmani Z.
      • Haghshenas M.
      • Azizi S.
      Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission [published online April 17, 2020].
      Di Mascio et al
      • Di Mascio D.
      • Khalil A.
      • Saccone G.
      • et al.
      Outcome of coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis [published online March 25, 2020].
      reported increased perinatal mortality and higher rates of neonatal intensive care unit admissions, but all neonates tested negative for SARS-CoV-2 infection. Chen et al
      • 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.
      confirmed no morphologic changes related to infection in 3 placentas of COVID-19–positive mothers. All 3 neonates also tested negative for SARS-CoV-2. Although these findings are consistent with reports suggesting minimal to no risk of vertical transmission,
      • Li Y.
      • Zhao R.
      • Zheng S.
      • et al.
      Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China.
      ,
      • 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.
      ,
      • Schwartz D.A.
      • Graham A.L.
      Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections [published online April 7, 2020].
      Penfield et al
      • Penfield C.A.
      • Brubaker S.G.
      • Limaye M.A.
      • et al.
      Detection of SARS-COV-2 in placental and fetal membrane samples [published online May 8, 2020].
      reported positive SARS-CoV-2 results in 3 of 11 placental swabs from COVID-19–positive mothers. All 3 of the neonates also tested negative. Whether vertical transmission truly occurred, or whether neonates were swabbed too early (during the incubation period) is unclear.
      Shah et al
      • Shah P.S.
      • Diambomba Y.
      • Acharya G.
      • Morris S.K.
      • Bitnun A.
      Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates.
      published a well-structured classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates that gives the opportunity to consider the risk of maternal to fetal or neonatal transmission beyond just vertical transmission. The classification includes congenital infection from intrauterine death/stillbirth, congenital infection in live-born infants, neonatal infection acquired intrapartum, or neonatal infection acquired postnatally. In addition, several professional societies have provided guidelines for the management of COVID-19 during pregnancy. The overall summaries from these professional bodies are consistent, with some variation in the strength of recommendations.
      • Narang K.
      • Ibirogba E.R.
      • Elrefaei A.
      • Trad A.T.A.
      • Theiler R.
      • Nomura R.
      • et al.
      SARS-CoV-2 in pregnancy: a comprehensive summary of current guidelines.

      Current Guidelines for COVID-19 Management in Pregnancy

      Professional perinatal societies, including the Society for Maternal-Fetal Medicine (SMFM)
      • Boelig R.C.
      • Saccone G.
      • Bellussi F.
      • Berghella V.
      MFM Guidance for COVID-19 [published online March 19, 2020].
      ,
      • Boelig R.C.
      • Manuck T.
      • Oliver E.A.
      • et al.
      Labor and delivery guidance for COVID-19.
      and the American College of Obstetricians and Gynecologists (ACOG)
      American College of Obstetricians and Gynecologists
      Novel coronavirus COVID-19, a practice advisory.
      ,
      American College of Obstetricians and Gynecologists
      COVID-19 FAQs for obstetrician-gynecologists, obstetrics.
      from the United States, the Royal College of Obstetricians and Gynaecologists (RCOG)
      Royal College of Obstetricians and Gynaecologists
      Coronavirus (COVID-19) infection in pregnancy: information for healthcare professionals.
      from the United Kingdom, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG),
      • Poon L.C.
      • Yang H.
      • Lee J.C.S.
      • et al.
      ISUOG interim guidance on 2019 novel coronavirus infection during pregnancy and puerperium: information for healthcare professionals.
      the Centers for Disease Control and Prevention (CDC),
      Centers for Disease Control and Prevention
      Information for healthcare providers: COVID-19 and pregnant women.
      ,
      Centers for Disease Control and Prevention
      Pregnancy & breastfeeding: information about coronavirus disease.
      and the World Health Organization (WHO), have developed guidelines for the care of pregnant patients. Herein we summarize the most current guidelines, updated as of April 22, 2020. A total of 9 papers were identified from 6 societies: SMFM, ACOG, RCOG, ISUOG, CDC, and WHO.
      A summary of these guidelines is outlined in Table 2, divided into three sections: antepartum, intrapartum, and postpartum care. The guidelines provide practical management recommendations that institutions can adapt to their infrastructures and resource availability. The recommendations from the SMFM focus on high-risk pregnancies, and those from the ACOG and the RCOG focus on all pregnancies. The WHO and the CDC focus on recommendations that can be generalized across all patient populations, and ISUOG focuses on sonography and care of ultrasound equipment.
      Table 2Consensus on Recommendations Classified by Phase of Care of Pregnancy
      Antepartum care
      TitlePrenatal infection screeningPrenatal appointmentUS frequencyUS equipment/patient roomsAntenatal surveillanceAntenatal corticosteroidsGBS screening
      Consensus on recommendationsTriage symptomatic patients via telehealth

      Test anyone with new flulike symptoms

      Prioritize high-risk patients: older, immunocompromised, advanced HIV, homeless, hemodialysis

      Use drive-through or standalone testing area

      All suspected cases should be screened using qRT-PCR

      Symptomatic patients should be treated as positive until results are back

      Repeat testing in 24 h if negative but still high suspicion
      Elective and nonurgent appointments should be postponed or completed by telehealth

      Encourage use of telehealth for all visits

      HCW meetings should be conducted via virtual/audio platform, if feasible

      Reserve F2F visits for 11-13, 20, 28, 36 wk and weekly after 37 wk

      Complete laboratory tests and US on same visit day

      Limit support person at outpatient F2F visits
      Consensus: Continue US as medically indicated when possible

      SMFM suggestions: Combine dating and nuchal translucency US in first trimester

      Anatomy scan at 20-22 wk

      Consider stopping serial CL after anatomy

      US if transvaginal US CL ≥35 mm, previous preterm birth at >34 wk

      Body mass index >40: schedule at 22 wk to reduce risk of suboptimal views/need for follow-up

      Single growth F/U at 32 wk

      Low-lying placenta F/U 34-36 wk
      Must be cleaned with disinfectant per manufacturer guidelines after EVERY use

      Deep clean all instruments and room in the case of a positive patient
      Reserve for medically indicated screening

      Limit NST <32 wk

      Twice weekly NST only for fetal growth restriction with abnormal umbilical arterial Doppler studies, complicated monochorionic twins, or Kell-sensitized patients with significant titers

      If patient needs US, perform biophysical profile instead of NST

      Kick counts instead of NST for low-risk patients

      Daily NST if patient hospitalized
      Should continue if <34 wk, even if tested positive for COVID-19

      Balance risks and benefits for 34 0/7 to 36 6/7 wk

      Other modifications should be individualized
      As indicated between 36 0/7 and 37 6/7 wk gestation

      Consider grouping with other visits in the same time frame

      Patients can self-collect with proper instructions if the resources and infrastructure allow
      Intrapartum care
      TitlePredelivery preparation/screeningDelivery locationDelivery timeMode of deliverySupport personObstetric analgesia and anesthesiaOxygen useSecond stage of laborThird stage of laborUmbilical cord clampingPPE
      Consensus on recommendationsSocial distancing and off work for 2 wk before anticipated delivery (start at ∼37 wk)

      Screen patient and partner on phone day before admission

      Limit HCW staffing to only essential staff
      Designated isolation room, for suspected or confirmed cases of COVID-19Based on routine obstetric indications

      Early delivery should be considered for critically ill patients

      No contraindications to IOL unless there are limited beds
      Based on routine obstetric indications

      COVID-19 infection is not an indication for CD

      Expedite delivery by CD in the setting of fetal distress or maternal deterioration

      Water births should be avoided
      Allowed 1 consistent asymptomatic support personNo evidence against regional or general anesthesia

      Epidural analgesia is recommended to women with suspected or confirmed COVID-19 to minimize the need for GA if urgent delivery is needed

      Avoid use of nitrous oxide
      Do not use oxygen for intrauterine resuscitation

      Consider aerosolizing

      HCWs must wear appropriate PPE (N95)
      Do not delay pushing

      Consider shortening with operative delivery to minimize aerosolization and maternal respiratory effort
      Consider active management to reduce blood loss (national blood shortage)Delayed cord clamping is still recommended in the absence of contraindications

      Avoid delayed cord clamping in confirmed and suspected cases
      -Asymptomatic or negative patients: Patient and provider wear surgical mask

      Aerosolizing procedures: N95 for patient and N95, gown, gloves, face shield for provider
      Postpartum care
      TitlePlacental and fetal tissueLength of stayBreastfeedingSkin to skinPostpartum pain controlPostpartum visit
      Consensus on recommendationsISUOG recommendations: Should be handled as infectious tissue in positive patients

      Consider qRT-PCR on placenta
      Expedited discharge should be considered if stable.

      VD → 1 d

      CD → 2 d
      Limited evidence to advise against breastfeeding

      Advise patients to (1) practice respiratory hygiene during feeding, (2) wear a mask, (3) wash hands before and after touching the baby, (4) routinely clean and disinfect surfaces they have touched

      During separation, encourage dedicated breast pumping
      Routine precautionary separation of a healthy baby and mother is not advised

      Encourage good hygiene and appropriate PPE for COVID-19–positive patients
      No contraindication to NSAID useEncourage telehealth for postpartum visit

      Limit F2F visits only for medically necessary concerns
      CD = cesarean delivery; CL = cervical length; COVID-19 = coronavirus disease 2019; F2F = face to face; F/U = follow-up; GA = general anesthesia; GBS = group B streptococcus; HCW = health care worker; HIV = human immunodeficiency virus; IOL = induction of labor; ISUOG = International Society of Ultrasound in Obstetrics and Gynecology; NSAID = nonsteroidal anti-inflammatory drug; NST = nonstress test; PPE = personal protective equipment; qRT-PCR = quantitative reverse transcriptase polymerase chain reaction; SMFM = Society for Maternal-Fetal Medicine; US = ultrasonography; VD = vaginal delivery.

      Prenatal/Antepartum Care

      The consensus among all societies recommends the use of telehealth for prenatal visits. Ultrasound and antenatal surveillance should be combined with visits for laboratory tests or prenatal care. Patients should be screened for symptoms, travel history, and contact history before any face-to-face visits; those who are symptomatic or meet the criteria should undergo testing for SARS-CoV-2 using qRT-PCR. Appropriate personal protective equipment (PPE) should be worn by patients and health care workers. Administration of antenatal corticosteroids for fetal lung maturation should still be considered if a pregnancy is between 24 0/7 and 33 6/7 weeks’ gestation, but the risk/benefit balance needs to be discussed by the multidisciplinary team. Data on the use of corticosteroids during late preterm (34 0/7 to 36 6/7 weeks) are still controversial, but routine administration is not advised.
      • Boelig R.C.
      • Manuck T.
      • Oliver E.A.
      • et al.
      Labor and delivery guidance for COVID-19.

      Intrapartum Care

      Institutions should have a designated area for triaging, screening, and admitting SARS-CoV-2–positive patients. The mode and timing of delivery should follow routine obstetric indications, keeping in mind that COVID-19 alone is not an indication for CD, unless there is fetal distress or deteriorating maternal clinical status. Societies recommend that only 1 consistent healthy asymptomatic individual providing support should be present during labor and delivery. Aerosol-generating procedures, including forceful pushing during the second stage of labor and oxygen supplementation for intrauterine resuscitation, should be limited and appropriate PPE (N95) worn. Water births are contraindicated due to the limited ability to monitor mother and baby, and the risk of fecal transmission.

      Postpartum Care

      Breastfeeding should not be discouraged, and mother and baby separation is not advised, unless the mother is acutely ill. Mothers are advised to follow appropriate respiratory hygiene by wearing masks during skin-to-skin contact and breastfeeding. Mothers should wash hands before handling their babies or touching pumps or bottles and should avoid coughing while their babies are feeding. All surfaces and breast pumps should be sanitized after each use. In an effort to limit infection exposure, hospital length of stay should be decreased to 1 day for vaginal deliveries and 2 days for CDs. Postpartum visits should be performed through telehealth and patients advised to continue compliance with social distancing after discharge. The method of telehealth should be individualized based on institution resources and availability.

      Implications of COVID-19 in Special Pregnant Patient Populations

      Evidence on the potential outcomes of SARS-CoV-2 infection in pregnancies already complicated by congenital anomalies is lacking. Given the severity of some potentially life-threatening congenital conditions as well as the disease-altering effects of fetal interventions, these procedures are considered urgent essential medical services. Therefore, necessary adjustments to the prenatal evaluation and selection of fetal intervention candidates have been proposed to better adapt this essential service to the ongoing pandemic. Perhaps the most important factor to consider is the potential risk of vertical transmission induced by the invasive nature of these procedures.
      There is no definitive evidence of in utero transmission from SARS-CoV-2 to date. Some case reports
      • Yu N.
      • Li W.
      • Kang Q.
      • et al.
      Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study.
      ,
      • Dong L.
      • Tian J.
      • He S.
      • et al.
      Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn.
      ,
      • Zamaniyan M.
      • Ebadi A.
      • Aghajanpoor Mir S.
      • Rahmani Z.
      • Haghshenas M.
      • Azizi S.
      Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission [published online April 17, 2020].
      have reported possible vertical transmission due to positive amniotic fluid SARS-CoV-2 PCR test results, but most of the limited patient series reported in the literature indicate a low to negligible risk.
      • Deprest J.
      • Van Ranst M.
      , Lannoo L, et al. SARS-CoV2 (COVID-19) infection: is fetal surgery in times of national disasters reasonable [published online April 11, 2020]?.
      ,
      • Karimi-Zarchi M.
      • Neamatzadeh H.
      • Dastgheib S.A.
      • et al.
      Vertical transmission of coronavirus disease 19 (COVID-19) from infected pregnant mothers to neonates: a review [published online April 2, 2020].
      Evidence is rapidly accumulating, and this consensus may change as more patients with COVID-19 in pregnancy are reported.

      Prenatal Diagnosis

      In the event of a suspected or confirmed fetal anomaly, additional evaluation (fetal echocardiography, amniocentesis, chorionic villus sampling [CVS], or cordocentesis) may be indicated to identify patients who could benefit from fetal interventions.
      Prenatal diagnostic evaluations may be classified as invasive or noninvasive depending on the risk of vertical transmission and exposure of patients and health care workers to SARS-CoV-2. Imaging studies, including ultrasonography and fetal echocardiography, are considered noninvasive (with no risk of vertical transmission), but specific precautions, including hygiene and use of appropriate PPE, should be applied to the patient and examiner, as well as proper care of the sonogram and ultrasound suite.
      • Abu-Rustum R.S.
      • Akolekar R.
      • Sotiriadis A.
      • et al.
      ISUOG consensus statement on organization of routine and specialist obstetric ultrasound services in the context of COVID-19 [published online March 31, 2020].
      For patients with suspected or confirmed SARS-CoV-2 infection, consideration should be given to postponing prenatal imaging until asymptomatic, if safely feasible.
      Invasive diagnostic tests (CVS, amniocentesis, and cordocentesis) are associated with a theoretical risk of vertical transmission because these procedures may directly correlate with the risk of fetomaternal hemorrhage.
      • Deprest J.
      • Van Ranst M.
      , Lannoo L, et al. SARS-CoV2 (COVID-19) infection: is fetal surgery in times of national disasters reasonable [published online April 11, 2020]?.
      Chorionic villus sampling, which is usually performed between 10 0/7 and 13 6/7 weeks’ gestation, may be offered to patients with a low risk of SARS-CoV-2 infection (asymptomatic or negative screening result). For symptomatic patients with suspected or confirmed SARS-CoV-2, invasive diagnostic tests can be delayed if safely feasible. If genetic testing cannot be delayed, amniocentesis (usually performed after 14 0/7 weeks’ gestation) should be performed instead of CVS owing to the theoretical lower risk of vertical transmission if transplacental access is avoided. Amniocentesis can also be offered to all asymptomatic or confirmed SARS-CoV-2–negative patients.
      • Deprest J.
      • Van Ranst M.
      , Lannoo L, et al. SARS-CoV2 (COVID-19) infection: is fetal surgery in times of national disasters reasonable [published online April 11, 2020]?.
      Fetal blood sampling/transfusion is another invasive procedure with a theoretical risk of vertical transmission. This intervention may be offered to patients with confirmed negative SARS-CoV-2 PCR but should be delayed (if feasible and safe) in those who are symptomatic or positive for SARS-CoV-2.
      • Deprest J.
      • Van Ranst M.
      , Lannoo L, et al. SARS-CoV2 (COVID-19) infection: is fetal surgery in times of national disasters reasonable [published online April 11, 2020]?.

      Fetal Therapy

      The Mayo Clinic Fetal Center follows the recommendations of the North American Fetal Therapy Network (NAFTNet), which currently recommends that fetal interventions be provided as much as resources allow due to the time-sensitive nature of conditions amenable to fetal therapy.
      • Bahtiyar M.O.
      • Baschat A.
      • Deprest J.
      • et al.
      Fetal interventions in the setting of COVID-19 pandemic: statement from the North American Fetal Therapy Network (NAFTNet).
      Specific institutional policies may vary, but, in general, all fetal interventions that have been established as the standard of care (for select patients) should continue to be provided, taking the necessary perioperative precautions. Conversely, innovative or experimental procedures that are yet to show proven benefit should be individualized. In general, for patients with asymptomatic SARS-CoV-2 infection, fetal intervention can be offered. For symptomatic patients, it is recommended that fetal therapy be postponed until maternal conditions stabilize and patients have recovered from the disease. Some examples of fetal surgeries that are still currently offered at Mayo Clinic include fetoscopic laser ablation of placental anastomoses for twin-to-twin transfusion syndrome,
      • Ruano R.
      • Rodo C.
      • Peiro J.L.
      • et al.
      Fetoscopic laser ablation of placental anastomoses in twin-twin transfusion syndrome using 'Solomon technique.
      in utero repair of spina bifida,
      • Ruano R.
      • Daniels D.J.
      • Ahn E.S.
      • et al.
      In utero restoration of hindbrain herniation in fetal myelomeningocele as part of prenatal regenerative therapy program at Mayo Clinic.
      intrauterine fetal blood transfusion,
      • Lindenburg I.T.
      • van Kamp I.L.
      • Oepkes D.
      Intrauterine blood transfusion: current indications and associated risks.
      in utero intervention for lower urinary tract obstruction,
      • Ruano R.
      • Sananes N.
      • Wilson C.
      • et al.
      Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity.
      fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia,
      • Ruano R.
      • Yoshisaki C.T.
      • da Silva M.M.
      • et al.
      A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia.
      in utero procedure for fetal tumors associated with hydrops,
      • Nassr A.A.
      • Ness A.
      • Hosseinzadeh P.
      • et al.
      Outcome and treatment of antenatally diagnosed nonimmune hydrops fetalis.
      and in utero intervention for severe congenital heart defects.
      • Said S.M.
      • Qureshi M.Y.
      • Taggart N.W.
      • et al.
      Innovative 2-step management strategy utilizing EXIT procedure for a fetus with hypoplastic left heart syndrome and intact atrial septum.

      Treatment of COVID-19 in Pregnant Patients

      No drugs have been proved to be effective and safe to use for the treatment of COVID-19 to date. Table 3 outlines the medications or therapies used in various research protocols under investigation, as well as their safety for use in pregnancy. In addition, because the pro-coagulatory state of pregnancy may contribute to thrombotic risks associated with COVID-19, thromboprophylaxis, which is currently advised for patients with COVID-19,
      • Thachil J.
      • Tang N.
      • Gando S.
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID-19.
      should be considered for pregnant patients as well.
      Table 3Treatment Options for COVID-19
      Treatment strategyMechanism of actionEffectivenessSafety in pregnancy
      HCQ/chloroquine
      NIH
      COVID-19 treatment guidelines.
      Reduces inflammatory cytokines
      • Zumla A.
      • Chan J.F.
      • Azhar E.I.
      • Hui D.S.
      • Yuen K.Y.
      Coronaviruses - drug discovery and therapeutic options.
      ; interferes with ACE2 receptor synthesis.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ,
      • Vincent M.J.
      • Bergeron E.
      • Benjannet S.
      • et al.
      Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.
      Reduction of body temperature recovery time and cough remission, pneumonia recovery, improved CT findings, nasopharyngeal viral clearance.
      • Chen J.
      • Liu D.
      • Liu Let al
      A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19).
      • Gautret P.
      • Lagier J.-C.
      • Parola P.
      • et al.
      Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study [published online April 11, 2020].
      • Li Y.
      • Xie Z.
      • Lin W.
      • et al.
      An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI) [published online April 15, 2020].
      Generally considered safe in pregnancy and frequently used for patients with autoimmune disease.
      Food and Drug Administration
      Plaquenil® hydroxychloroquine sulfate, USP.
      Efficacy unproven. Concern for prolonged QTc.
      HCQ and azithromycinReduction of viral replication and IL-6 and IL-8 production.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ,
      • Gielen V.
      • Johnston S.L.
      • Edwards M.R.
      Azithromycin induces anti-viral responses in bronchial epithelial cells.
      Improved nasopharyngeal viral clearance.
      • Gautret P.
      • Lagier J.-C.
      • Parola P.
      • et al.
      Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study [published online April 11, 2020].
      HCQ: as above.

      Azithromycin: considered safe.
      Food and Drug Administration
      Zithromax® (azithromycin tablets) and (azithromycin for oral suspension).
      Lopinavir/rotinavirInhibition of 3-chymotrypsin-like protease.
      • Zumla A.
      • Chan J.F.
      • Azhar E.I.
      • Hui D.S.
      • Yuen K.Y.
      Coronaviruses - drug discovery and therapeutic options.
      ,
      • Ul Qamar M.T.
      • Alqahtani S.M.
      • Alamri M.A.
      • Chen L.-L.
      Structural basis of SARS-CoV-2 3CL(pro) and anti-COVID-19 drug discovery from medicinal plants [published online March 26, 2020].
      ,
      • Liu X.
      • Wang X.-J.
      Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines.
      Reduced mortality.
      • Cao B.
      • Wang Y.
      • Wen D.
      • et al.
      A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.
      Good safety profile in pregnant patients with HIV.
      NIH. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States.
      RemdesivirInhibition of viral RNA-dependent RNA polymerase.
      • Warren T.K.
      • Jordan R.
      • Lo M.K.
      • et al.
      Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.
      Clinical trial still underway. Reduction in duration of hospital stay and mortality.
      • Marchione M.
      A 1st: US study finds Gilead drug works against coronavirus.
      Not yet FDA approved.
      AnakinraIL-1 inhibitor.Clinical trial still underway.Insufficient data to determine risk in pregnancy.

      Anakinra. Drugs.com website, https://www.drugs.com/ppa/anakinra.html#moreResources. Accessed July 8, 2020.

      SiltuximabHuman-mouse chimeric monoclonal antibody against IL-6.Improvement in clinical condition in one-third of patients.
      • Gritti G.
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      • Ripamonti D.
      • et al.
      Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support [published online May 22, 2020].
      Insufficient data to determine risk in pregnancy.
      National Institutes of Health. Table 3b. Host modifiers and immune-based therapy under evaluation for treatment of COVID-19.
      SarilumabRecombinant IL-6 receptor monoclonal antibody.No data yet from randomized clinical trials or observational studies.
      NIH
      COVID-19 treatment guidelines.
      Insufficient data to determine risk in pregnancy.
      NIH
      COVID-19 treatment guidelines.
      TocilizumabRecombinant IL-6 receptor monoclonal antibody.No data yet from randomized clinical trials or observational studies.
      NIH
      COVID-19 treatment guidelines.
      Insufficient data to determine risk in pregnancy.
      NIH
      COVID-19 treatment guidelines.
      InterferonAntiviral cytokines.No data yet from randomized clinical trials or observational studies.
      NIH
      COVID-19 treatment guidelines.
      Varying adverse effect profiles in various preparations.
      CorticosteroidAnti-inflammatory actions.
      • Barnes P.J.
      How corticosteroids control inflammation: Quintiles Prize Lecture 2005.
      Reduced mortality in patients with ARDS.
      • Wu C.
      • Chen X.
      • Cai Y.
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China [published online March 13, 2020].
      Faster improvement in patients with severe COVID pneumonia.
      • Wang Y.
      • Jiang W.
      • He Q.
      • et al.
      Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China [published online March 12, 2020].
      Considered safe, approved for lung maturation in preterm birth.
      American College of Obstetricians and Gynecologistsy
      Practice advisory: novel coronavirus 2019 (COVID-19).
      ACE inhibitors or angiotensin receptor blockersACE2 receptor is the cell receptor for viral entry for COVID-19 virus.
      • Chan J.F.
      • Kok K.H.
      • Zhu Z.
      • et al.
      Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.
      ,
      • Gralinski L.E.
      • Menachery V.D.
      Return of the coronavirus: 2019-nCoV.
      No data yet from randomized clinical trials or observational studies
      NIH
      COVID-19 treatment guidelines.
      Contraindicated in pregnancy.
      • Food and Drug Aministration
      Angiotensin-converting enzyme inhibitors and pregnancy: FDA public health advisory.
      ,
      • Barreras A.
      • Gurk-Turner C.
      Angiotensin II receptor blockers.
      Convalescent plasmaConvalescent plasma from recently recovered donors targeting COVID-19 virus.10 Patients with clinically severe COVID-19 were given 200 mL of convalescent plasma. Increase in oxyhemoglobin saturation by day 3, and improved lymphocyte count as well as CRP levels were noted.Several studies are currently underway.
      • Duan K.
      • Liu B.
      • Li C.
      • et al.
      Effectiveness of convalescent plasma therapy in severe COVID-19 patients.
      No data on safety in pregnancy. However, specific immunoglobulins as for varicella are used in pregnancy.
      National Institutes of Health. Table 3b. Host modifiers and immune-based therapy under evaluation for treatment of COVID-19.
      ACE = angiotensin-converting enzyme; ARDS, acute respiratory distress syndrome; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; CT = computed tomography; FDA = Food and Drug Administration; HCQ = hydroxychloroquine; HIV = human immunodeficiency virus; IL = interleukin.
      There are 6 candidate vaccines under phase 1 or 2 clinical trials and 77 more candidate vaccines in preclinical evaluation as of April 23, 2020.
      • World Health Organization
      Draft landscape of COVID-19 candidate vaccines.
      Many vaccines use the spike protein (S protein) as their platform and present as forms of recombinant protein-based vaccines, live attenuated vaccines, inactive viral vaccines, and viral-vector–based vaccines.
      • Amanat F.
      • Krammer F.
      SARS-CoV-2 vaccines: status report.
      Live attenuated vaccines are generally contraindicated in pregnancy, but exceptions may be made during pandemic situations (exception for smallpox vaccine). As with any drug under development, assessment for safety in pregnancy is conducted after initial safety data become available from clinical studies. Although it is essential to guarantee safety, an unfortunate impact of delaying research in pregnancy is that vaccinations for pregnant women may also be delayed. This is especially problematic during a pandemic or epidemic, as evident from lessons learned from the Ebola outbreak.
      • Gomes M.F.
      • de la Fuente-Núñez V.
      • Saxena A.
      • Kuesel A.C.
      Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials.

      Future Perspectives

      The presented data are preliminary, collected over 4 months and likely to change once large data sets become available. However, the projected course of COVID-19 on the morbidity and mortality of pregnant patients during these challenging times is unprecedented. Racial disparities are known to exist in the obstetric literature.
      ACOG Committee Opinion No
      649: racial and ethnic disparities in obstetrics and gynecology.
      Global health crises subject racial and ethnic minorities, as well as patients with immunocompromised comorbidities, to poorer outcomes. We envision that national and international perinatal societies will focus on the unique challenges faced by vulnerable patient populations that are burdened with physical, emotional, and social crises, with a focus on improving outcomes for all pregnant patients.

      Conclusion

      Given differing physiology during gestation, pregnancy represents a vulnerable state that may be associated with a greater risk of SARS-CoV-2 infection and subsequent worse COVID-19 outcomes. Global efforts to fast track publication of data on COVID-19 in pregnancy, albeit limited, have allowed us to form a framework to care for these patients. Early reports suggest higher rates of preeclampsia and other pregnancy-related complications with SARS-CoV-2 infection during pregnancy, thus adding urgency to the pursuit of research into optimal COVID-19 treatment and preventive strategies during pregnancy.

      Acknowledgments

      We thank Margaret A. McKinney, MS, for assistance with media and illustration support.

      Supplemental Online Material

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      Linked Article

      • In the Limelight: August 2020
        Mayo Clinic ProceedingsVol. 95Issue 8
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          As in the June and July 2020 issues, this month’s feature highlights five articles on COVID-19 that appear in the current print and online issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings’ YouTube Channel ( https://youtu.be/xWJNrf2_Dr0 ).
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