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COVID-19 in pregnancy: a systematic review of chest CT findings and associated clinical features in 427 patients

  • Author Footnotes
    1 These authors contributed equally to the work and should be considered as co-first authors.
    Rachel R. Oshay
    Footnotes
    1 These authors contributed equally to the work and should be considered as co-first authors.
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America

    Department of Integrative Anatomical Sciences, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Author Footnotes
    1 These authors contributed equally to the work and should be considered as co-first authors.
    Michael Y.C. Chen
    Footnotes
    1 These authors contributed equally to the work and should be considered as co-first authors.
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America

    Department of Integrative Anatomical Sciences, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Brandon K.K. Fields
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Natalie L. Demirjian
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America

    Department of Integrative Anatomical Sciences, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Ryan S. Lee
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Daniel Mosallaei
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America
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  • Ali Gholamrezanezhad
    Correspondence
    Corresponding author at: Department of Radiology, Division of Emergency Radiology, Keck School of Medicine, University of Southern California, 1500 San Pablo Street, Los Angeles, CA 90033, United States of America.
    Affiliations
    Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States of America

    Department of Radiology, Los Angeles, CA 90033, United States of America
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to the work and should be considered as co-first authors.

      Highlights

      • Pregnant patients with COVID-19 presented less frequently with bilateral lung involvement than non-pregnant adults.
      • Pregnant patients with COVID-19 frequently presented with consolidation (40.9%) and pleural effusion (30.0%).
      • Adoption of a standardized reporting lexicon is recommended to avoid inconsistent use of morphological descriptors.

      Abstract

      Purpose

      Our purpose was to conduct a comprehensive systematic review of all existing literature regarding imaging findings on chest CT and associated clinical features in pregnant patients diagnosed with COVID-19.

      Materials & methods

      A literature search was conducted on April 21, 2020 and updated on July 24, 2020 using PubMed, Embase, World Health Organization, and Google Scholar databases. Only studies which described chest CT findings of COVID-19 in pregnant patients were included for analysis.

      Results

      A total of 67 articles and 427 pregnant patients diagnosed with COVID-19 were analyzed. The most frequently encountered pulmonary findings on chest CT were ground-glass opacities (77.2%, 250/324), posterior lung involvement (72.5%, 50/69), multilobar involvement (71.8%, 239/333), bilateral lung involvement (69.4%, 231/333), peripheral distribution (68.1%, 98/144), and consolidation (40.9%, 94/230). Pregnant patients were also found to present more frequently with consolidation (40.9% vs. 21.0–31.8%) and pleural effusion (30.0% vs. 5.0%) in comparison to the general population. Associated clinical features included antepartum fever (198 cases), lymphopenia (128 cases), and neutrophilia (97 cases). Of the 251 neonates delivered, 96.8% had negative RT-PCR and/or IgG antibody testing for COVID-19. In the eight cases (3.2%) of reported neonatal infection, tests were either conducted on samples collected up to 72 h after birth or were found negative on all subsequent RT-PCR tests.

      Conclusion

      Pregnant patients appear to present more commonly with more advanced COVID-19 CT findings compared to the general adult population. Furthermore, characteristic laboratory abnormalities found in pregnant patients tended to mirror those found in the general patient population. Lastly, results from neonatal testing suggest a low risk of vertical transmission.

      Abbreviations:

      WHO (World Health Organization), COVID-19 (Coronavirus Disease 2019), RT-PCR (Reverse Transcriptase Polymerase Chain Reaction), CT (Computed Tomography), SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), GGOs (Ground-Glass Opacities), NIH (National Institutes of Health), CRP (C-reactive protein), MERS (Middle East Respiratory Syndrome)

      Keywords

      1. Introduction

      On New Year's Eve 2019, Chinese national officials reported an outbreak of a highly-contagious pneumonia of unknown cause in Wuhan, Hubei Province, China to the World Health Organization (WHO).
      By mid-February, the WHO named the disease caused by this novel infectious agent Coronavirus Disease 2019 (COVID-19).
      Although data from the WHO suggest that as many as 80% of infections are mild or asymptomatic, common symptoms when present often include shortness of breath, fever, lethargy, sore throat, headache, chest pain, diarrhea, ageusia, and anosmia.
      Extra-pulmonary features can include renal, gastrointestinal, hepatic, cardiac, neurological, and hematological manifestations.
      • Behzad S.
      • Aghaghazvini L.
      • Radmard A.R.
      • Gholamrezanezhad A.
      Extrapulmonary manifestations of COVID-19: radiologic and clinical overview.
      Before reverse transcriptase polymerase chain reaction (RT-PCR) test kits became widely available, chest computed tomography (CT) was used in some settings as a tool to confirm diagnosis and track progression of disease.
      • Fang Y.
      • Zhang H.
      • Xie J.
      • et al.
      Sensitivity of chest CT for COVID-19: comparison to RT-PCR.
      • Ai T.
      • Yang Z.
      • Hou H.
      • et al.
      Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases.
      • Salehi S.
      • Abedi A.
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      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients.
      • Hosseiny M.
      • Kooraki S.
      • Gholamrezanezhad A.
      • Reddy S.
      • Myers L.
      Radiology perspective of coronavirus disease 2019 (COVID-19): lessons from severe acute respiratory syndrome and Middle East respiratory syndrome.
      • Davarpanah A.H.
      • Mahdavi A.
      • Sabri A.
      • et al.
      Novel screening and triage strategy in Iran during deadly coronavirus disease 2019 (COVID-19) epidemic: value of humanitarian teleconsultation service.
      • Demirjian N.L.
      • Fields B.K.K.
      • Song C.
      • et al.
      Impacts of the coronavirus disease 2019 (COVID-19) pandemic on healthcare workers: a nationwide survey of United States radiologists.
      • Demirjian N.L.
      • Fields B.K.K.
      • Gholamrezanezhad A.
      Role of chest CT in resource-driven healthcare systems.
      • Fields B.K.K.
      • Demirjian N.L.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19) diagnostic technologies: a country-based retrospective analysis of screening and containment procedures during the first wave of the pandemic.
      The most common features on CT imaging of patients in the general population with COVID-19 are multifocal, patchy, ground-glass opacities (GGOs) with or without superimposed consolidation in a peripheral or posterior distribution.
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients.
      ,
      • Han R.
      • Huang L.
      • Jiang H.
      • Dong J.
      • Peng H.
      • Zhang D.
      Early clinical and CT manifestations of coronavirus disease 2019 (COVID-19) pneumonia.
      Pregnant patients are a unique population of interest during the COVID-19 pandemic as they are typically young, otherwise-healthy individuals; however, they also experience an altered immunological state due to their expectancy. In 2003, pregnant patients who contracted Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) were found to be at increased risk for spontaneous miscarriage, preterm labor, and maternal death. However, follow-up testing on neonates postnatally was unable to detect serologic evidence of vertical transmission in select cohorts.
      • Wong S.F.
      • Chow K.M.
      • Leung T.N.
      • et al.
      Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome.
      Currently, there are limited data on COVID-19 in pregnant patients, and potential for vertical transmission remains unclear.
      What we know and don't know about coronavirus and pregnancy. What we know don't know coronavirus pregnancy.
      While many guidelines suggest avoidance of ionizing radiation in pregnancy, appropriate shielding and low-dose protocols may allow for relatively safe use of chest CT for situations in which such investigations are clinically indicated.
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      • Radpour A.
      • Sedaghat A.
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      Proposed imaging guidelines for pregnant women suspected of having COVID-19.
      As much of the literature regarding this unique patient population currently remains limited to case reports and case series, the primary purpose of this systematic review was to consolidate the existing knowledge on manifestations of COVID-19 in pregnant patients into a single report. We aimed to identify the most common laboratory abnormalities and imaging features on presenting chest CT, and to compare our findings with reported values in the general adult population.

      2. Materials and methods

      2.1 Literature and database search

      PubMed, Embase, WHO, and Google Scholar databases were queried using the same keyword search that included the terms “covid*” OR “ncov” OR “sars*” OR “2019-ncov” OR “coronavirus” AND “pregn*” OR “gestation*”. The search query was designed in consultation with an investigator experienced in database searches and subsequently revised by the other investigators. All searches were initially conducted on April 21, 2020 and updated on July 24, 2020. Given the recency of COVID-19 reported cases, searches were limited only to articles published in 2020.

      2.2 Qualification and study inclusion

      Two reviewers independently assessed each article for study appropriateness. Initially, articles were screened to remove duplicates and those not written in English. Only articles that included details on chest CT findings in pregnant patients diagnosed with SARS-CoV-2 infection were included in the study. All systematic reviews were screened to ensure that there was no subject overlap with any included case reports and case series. Of note, one article was withdrawn from print following the initial search and thus not tabulated in our final summative reporting.

      2.3 Risk of bias

      The quality of each article was independently rated by two reviewers as per the National Institutes of Health (NIH) Quality Assessment Tool for Case Series Studies (Table 1).

      Study quality assessment tools: quality assessment tool for case series studies. National Heart, Lung, and Blood Institute, National Institutes of Health website. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools [Accessed 22 May 2020].

      .
      Table 1Quality rating of articles using the National Institutes of Health (NIH) Quality Assessment Tool for Case Series Studies.

      Study quality assessment tools: quality assessment tool for case series studies. National Heart, Lung, and Blood Institute, National Institutes of Health website. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools [Accessed 22 May 2020].

      First author

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      Question
      NIH Quality Assessment Tool for Case Series Studies16 poses the following nine questions: 1 = Was the objective clearly stated?, 2 = Was the study population clearly and fully described, including a case definition?, 3 = Were the cases consecutive?, 4 = Were the subjects comparable?, 5 = Was the intervention clearly described?, 6 = Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants?, 7 = Was the length of follow-up adequate?, 8 = Were the statistical methods well-described?, 9 = Were the results well-described? Adapted from Salehi et al. (doi.org/10.2214/AJR.20.23034). NIH = National Institutes of Health.
      Overall rating
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      • Mo Y.
      • et al.
      Unlikely SARS-CoV-2 vertical transmission from mother to child: a case report.
      YesYesNANAYesNAYesNAYesFairFair
      Zeng
      • Zeng Y.
      • Lin L.
      • Yan Q.
      • et al.
      Update on clinical outcomes of women with COVID-19 during pregnancy.
      YesYesCDYesYesYesCDYesYesFairFair
      Wu
      • Wu Y.
      • Liu C.
      • Dong L.
      • et al.
      Viral shedding of COVID-19 in pregnant women.
      YesYesYesYesYesYesYesYesYesFairFair
      NIH = National Institute of Health, NR = not recorded, CD = cannot determine, NA = not applicable.
      a NIH Quality Assessment Tool for Case Series Studies

      Study quality assessment tools: quality assessment tool for case series studies. National Heart, Lung, and Blood Institute, National Institutes of Health website. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools [Accessed 22 May 2020].

      poses the following nine questions: 1 = Was the objective clearly stated?, 2 = Was the study population clearly and fully described, including a case definition?, 3 = Were the cases consecutive?, 4 = Were the subjects comparable?, 5 = Was the intervention clearly described?, 6 = Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants?, 7 = Was the length of follow-up adequate?, 8 = Were the statistical methods well-described?, 9 = Were the results well-described? Adapted from Salehi et al. (doi.org/10.2214/AJR.20.23034). NIH = National Institutes of Health.

      2.4 Synthesis and extraction of data

      All articles underwent data extraction and verification by two independent reviewers. For papers that included multiple CT scans per patient, only data from the first CT performed were used. As many articles did not explicitly list all CT findings present, data were supplemented with our own interpretations of images included in the text. Instances in which a given finding or laboratory value could not be definitively excluded with the textual information or imaging provided were not counted in the reported fractional denominators. The number of patients presenting with various clinical findings and laboratory aberrations, such as elevated C-reactive protein (CRP), lymphopenia, and neutrophilia, was also tabulated. These values were compared to reference ranges adjusted for physiological alterations in pregnancy.
      • Abbassi-Ghanavati M.
      • Greer L.G.
      • Cunningham F.G.
      Pregnancy and laboratory studies: a reference table for clinicians.

      3. Results

      3.1 Overview of included studies

      Once the literature searches were completed and duplicate records were removed, a total of 1737 records were identified for initial screening. After further review, a finalized total of 67 published studies were included in the quantitative data extraction (Fig. 1). Data were extracted from a total of 427 pregnant patients, all of whom were admitted to hospital for acute care related to COVID-19 from December 2019 to July 2020. The average reported age was 30.4 years, with a range of 17 to 49 years. In total, eight maternal deaths were reported.
      Fig. 1
      Fig. 1Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram, showing study selection process. Embase is a product of Elsevier. WHO = World Health Organization.
      Adapted from Salehi et al. (doi.org/10.2214/AJR.20.23034).

      3.2 Chest CT manifestations

      All 427 patients underwent chest CT for either diagnosis or clinical management as per standard-of-care protocols at their respective institutions. For 65 patients, low-dose protocol was explicitly reported. The remainder of cases did not specify radiation dosage. Many CT findings were reported using a wide array of nomenclature; for the purposes of the present study, these were further classified according to standard morphologic descriptors.
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients.
      ,
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19) imaging reporting and data system (COVID-RADS) and common lexicon: a proposal based on the imaging data of 37 studies.
      ,
      • Hansell D.M.
      • Bankier A.A.
      • MacMahon H.
      • McLoud T.C.
      • Müller N.L.
      • Remy J.
      Fleischner Society: glossary of terms for thoracic imaging.
      We found the following trends in CT manifestations: GGOs (77.2%, 250/324), posterior involvement (72.5%, 50/69), multilobar involvement (71.8%, 239/333), bilateral lung involvement (69.4%, 231/333), peripheral distribution (68.1%, 98/144), and consolidation (40.9%, 94/230). Patients without an explicit presence or absence of a given finding were excluded from the fractional denominators (Table 2, Table 3). Of note, pleural effusion was observed in 30.0% of cases.
      Table 2Common patterns and distributions on initial CT images of 427 pregnant patients with COVID-19.
      Imaging findingNo. of reported cases/total no. of patients% of report cases
      Bilateral involvement231/33369.4
      Unilateral involvement102/33330.6
      Multilobar involvement239/33371.8
      Peripheral distribution98/14468.1
      Central distribution11/1447.64
      Peripheral & central distribution35/14424.3
      Subpleural distribution24/6835.3
      Anterior involvement1/691.45
      Posterior involvement50/6972.5
      Anterior & posterior involvement18/6926.1
      Ground-glass opacities (GGOs)250/32477.2
      Consolidation94/23040.9
      Pleural effusion45/15030.0
      Table 3Additional findings on initial CT images of 427 pregnant patients with COVID-19.
      Imaging findingNo. of reported cases
      Opacities NOS64
      Fibrotic bands11
      Cardiomegaly/change in heart size4
      Vascular changes5
      Opacities NOS = opacities not otherwise specified.

      3.3 Extra-pulmonary manifestations/constitutional symptoms

      Several extra-pulmonary manifestations were also recorded. However, as many articles tended only to report pertinent positives and often did not explicitly indicate absence of a given abnormality, we were unable to tabulate exact proportions for these findings. Nevertheless, 150 patients were reported to present with elevated CRP, 128 patients with lymphopenia, 97 patients with neutrophilia, 73 patients with leukocytosis, 51 patients with elevated D-dimers, 24 patients with anemia, and 24 patients with elevated procalcitonin. Likewise, a total of 198 patients had documented fevers prior to delivery (antepartum), and 67 had fevers in the postpartum period. Additionally, 15 patients had gastrointestinal involvement/diarrhea, and 12 patients had cardiac involvement. Of those who experienced cardiac complications, a total of eight patients succumbed to cardiac arrest and were unable to be resuscitated. Three of these fatal cases were attributed to refractory hypotension, including one patient who experienced severe heart failure with an ejection fracture of 10–15% and another patient who experienced left-sided heart failure with an ejection fraction of 25%.
      • Shojaei S.
      • Kouchek M.
      • Miri M.M.
      • et al.
      Twin pregnant woman with COVID-19: a case report.
      • Uzel K.
      • Lakhno I.V.
      A mortal case of coronavirus disease in a pregnant diabetic woman. Clinical case.
      • Hantoushzadeh S.
      • Shamshirsaz A.A.
      • Aleyasin A.
      • et al.
      Maternal death due to COVID-19.
      In addition, one patient was found to have a nonfatal pericardial effusion
      • Ai L.
      • Wei J.
      • Wang S.
      • et al.
      COVID-19 is a risk factor for severe liver damage for patients with intrahepatic cholestasis of pregnancy: a case report.
      (Table 4).
      Table 4Extra-pulmonary and constitutional symptoms of 427 pregnant patients with COVID-19.
      ManifestationNo. of reported cases
      Elevated C-reactive protein (CRP)150
      Lymphopenia128
      Neutrophilia97
      Leukocytosis73
      Elevated D-dimers51
      Anemia24
      Elevated procalcitonin24
      Antepartum fever198
      Postpartum fever67
      Gastrointestinal involvement/diarrhea15
      Cardiac involvement12
      Maternal death8

      3.4 Neonatal outcomes

      A total of 298 patients gave birth during admission to 304 neonates, 85 of which were born prematurely. Gestational ages at the time of delivery ranged between 28 and 41.3 weeks (28–41+2 weeks), with an average gestational age of 35.2 weeks (~35+1 weeks). Of the 304 neonates, 251 were tested for SARS-CoV-2 infection by RT-PCR and/or IgG antibody testing, with a resulting 96.8% negative test rate. Eight cases (3.2%) of suspected neonatal infection were reported, six of which tested positive by RT-PCR and two of which tested positive by IgG antibody assay. The six positive RT-PCR tests were conducted on samples collected between 16 and 72 h postpartum. The two cases of positive IgG antibody assays subsequently tested negative on follow-up RT-PCR. Furthermore, testing of cord blood, placenta, breastmilk, and/or vaginal secretions was conducted in four of the eight cases, all of which were negative for the presence of SARS-CoV-2. The overall neonatal survival rate was 93.14%.

      4. Discussion

      In the era of COVID-19, pregnant patients pose as a uniquely susceptible and understudied population. While routine exposure to ionizing radiation is discouraged during pregnancy, current guidelines recommend that chest CT should not be withheld when clinically indicated as the radiation dose from a single scan remains sub-threshold to cause teratogenic effects when appropriate precautions are taken.
      • The Society for Maternal-Fetal Society (SMFM)
      • Dotters-Katz S.
      • Hughes B.L.
      Coronavirus (COVID-19) and pregnancy: what maternal-fetal medicine subspecialists need to know.
      • Kanne J.P.
      • Little B.P.
      • Chung J.H.
      • Elicker B.M.
      • Ketai L.H.
      Essentials for radiologists on COVID-19: an update-radiology scientific expert panel.
      • Copel J.
      • El-Sayed Y.
      • Heine R.P.
      • Wharton K.R.
      ACOG Committee opinion: guidelines for diagnostic imaging during pregnancy and lactation.
      At the beginning of the COVID-19 pandemic, chest CT scans were frequently used in many patients,
      • Demirjian N.L.
      • Fields B.K.K.
      • Song C.
      • et al.
      Impacts of the coronavirus disease 2019 (COVID-19) pandemic on healthcare workers: a nationwide survey of United States radiologists.
      • Demirjian N.L.
      • Fields B.K.K.
      • Gholamrezanezhad A.
      Role of chest CT in resource-driven healthcare systems.
      • Fields B.K.K.
      • Demirjian N.L.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19) diagnostic technologies: a country-based retrospective analysis of screening and containment procedures during the first wave of the pandemic.
      including those who were pregnant. As knowledge of the disease became more disseminated and RT-PCR testing kits were made more readily available, chest CT use has since been curtailed at many institutions. Nevertheless, despite a plethora of literature discussing imaging findings and clinical features of COVID-19 in the general adult population, specifics regarding disease presentations in the pregnant population are lacking. Thus, this systematic review represents one of the most comprehensive analyses of the existing literature regarding initial chest CT findings and associated clinical features of pregnant COVID-19 patients to date.
      In a systematic review of 919 adults, Salehi et al. found that 87.5% of patients demonstrated bilateral lung involvement, 76.0% demonstrated peripheral lesion distribution, and 80.4% demonstrated posterior lung involvement. Furthermore, 88.0% of their patients presented with GGOs and 31.8% presented with consolidation.
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients.
      Similarly, Liu et al. identified bilateral involvement in 79% of their non-pregnant patients, but only 21% of non-pregnant patients presented with evidence of consolidation.
      • Liu H.
      • Liu F.
      • Li J.
      • Zhang T.
      • Wang D.
      • Lan W.
      Clinical and CT imaging features of the COVID-19 pneumonia: focus on pregnant women and children.
      Compared with our results, these findings suggest that pregnant patients may have a slightly lower prevalence of bilateral lung involvement than the general population (69.4% vs. 79–87.5%), which is consistent with published data suggesting lower rates of bilateral disease in younger populations.
      • Katal S.
      • Johnston S.K.
      • Johnston J.H.
      • Gholamrezanezhad A.
      Imaging findings of SARS-CoV-2 infection in pediatrics: a systematic review of coronavirus disease 2019 (COVID-19) in 850 patients.
      Additionally, our results suggest that pregnant patients may present with lower rates of GGOs (77.2% vs. 88.0%) and higher rates of consolidation (40.9% vs. 21.0–31.8%) compared to the general population. These observations are further detailed in Table 5. Also of note, pregnant patients were found to have higher rates of pleural effusion when compared to that of the general population (30.0% vs 5.0%).
      • Ojha V.
      • Mani A.
      • Pandey N.N.
      • Sharma S.
      • Kumar S.
      CT in coronavirus disease 2019 (COVID-19): a systematic review of chest CT findings in 4410 adult patients.
      Currently, limited data exist on the baseline prevalence of pleural effusion in pregnancy. However, though pregnancy is a known risk factor for pleural effusion, our results still suggest a 3-fold higher prevalence of pleural effusion in COVID-19 pregnant patients when compared to preliminary observational data taken from an asymptomatic pregnant cohort.
      • Ngwenya S.
      Pleural diseases in pregnancy: aetiology and management.
      ,
      • Dikensoy E.
      • Balat O.
      • Dikensoy O.
      The prevalence of pleural effusion in pregnant women: a pilot study.
      Considering that consolidation and pleural effusion are indicative of more severe disease progression, our results suggest that pregnant patients may be more prone to presentation at advanced disease stages.
      • Ye Z.
      • Zhang Y.
      • Wang Y.
      • Huang Z.
      • Song B.
      Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review.
      Table 5Comparison between rates of imaging findings in pregnant patients and the general population.
      Imaging findingPregnant rate (%)General population rate (%)
      Bilateral involvement69.479.0–87.5
      Peripheral distribution68.176.0–100
      Posterior involvement72.580.4
      Multilobar involvement71.878.8
      Ground-glass opacities (GGOs)77.288.0
      Consolidation40.921.0–31.8
      Pleural effusion30.05.0
      The data referenced for the rate of occurrence of each imaging finding in the general COVID-19 patient population was obtained from Salehi et al., Liu et al., and Ojha et al.
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients.
      ,
      • Liu H.
      • Liu F.
      • Li J.
      • Zhang T.
      • Wang D.
      • Lan W.
      Clinical and CT imaging features of the COVID-19 pneumonia: focus on pregnant women and children.
      ,
      • Ojha V.
      • Mani A.
      • Pandey N.N.
      • Sharma S.
      • Kumar S.
      CT in coronavirus disease 2019 (COVID-19): a systematic review of chest CT findings in 4410 adult patients.
      One theory as to why pregnant patients may be more susceptible to severe progression of COVID-19 is that they may experience thoracic cage splaying and reduced functional residual capacity due to the expansive volume of the gravid uterus.
      • Ye Z.
      • Zhang Y.
      • Wang Y.
      • Huang Z.
      • Song B.
      Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review.
      ,
      • Lam C.M.
      • Wong S.F.
      • Leung T.N.
      • et al.
      A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome.
      In a study comparing pregnant and non-pregnant patients with SARS-CoV-1, two-thirds of deaths in the pregnant cohort occurred during the second or third trimester, coincident with the time when these physiological changes are most evident.
      • Lam C.M.
      • Wong S.F.
      • Leung T.N.
      • et al.
      A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome.
      These same changes could theoretically increase risk of developing severe complications of COVID-19 by reducing ability to clear secretions, which could in turn lead to a higher likelihood of developing consolidative pneumonia. Another theory is that altered immune functionality during pregnancy predisposes patients to acute pulmonary injury.
      • Lam C.M.
      • Wong S.F.
      • Leung T.N.
      • et al.
      A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome.
      ,
      • Lapinsky S.E.
      Acute respiratory failure in pregnancy.
      This could explain the fewer instances of GGOs and greater instances of consolidation seen in our cohort. The lungs of these particularly susceptible patients could be compensating with a stronger inflammatory response, which could in turn predispose to lesion progression to consolidation on CT imaging. Furthermore, most fatal cases in our cohort resulted from cardiac complications with low ejection fraction. Pregnancy is in and of itself a known risk factor for cardiomyopathy; however, as myocardial injury is also a known manifestation of COVID-19, it is possible that additive effects of disease may not just be limited to pulmonary complications and may in fact extend to other organ systems.
      • Behzad S.
      • Aghaghazvini L.
      • Radmard A.R.
      • Gholamrezanezhad A.
      Extrapulmonary manifestations of COVID-19: radiologic and clinical overview.
      ,
      • Elkayam U.
      • Akhter M.W.
      • Singh H.
      • et al.
      Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation.
      Of note, 150 patients in our cohort presented with elevated CRP levels (>10 mg/L), and 24 patients presented with elevated procalcitonin levels (>0.1 ng/mL). A small meta-analysis previously found that an increase in procalcitonin was correlated with advanced progression of COVID-19 by nearly fivefold
      • Lippi G.
      • Plebani M.
      Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis.
      ; however, only 2 of the 24 patients with elevated procalcitonin levels in our study eventually required mechanical ventilation, and 23 patients recovered fully. In addition, 51 patients exhibited elevated D-dimers ≥2.0 μg/mL. While elevated D-dimers have been associated with a greater morbidity and mortality in COVID-19,
      • Fields B.K.K.
      • Demirjian N.L.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19): an update on neurologic sequelae.
      • Lim W.S.
      • Macfarlane J.T.
      • Colthorpe C.L.
      Pneumonia and pregnancy.
      • Zhang L.
      • Yan X.
      • Fan Q.
      • et al.
      D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      • Magro C.
      • Mulvey J.J.
      • Berlin D.
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      all 51 patients with elevated D-dimer levels in our study population made a complete recovery. As physiological pregnancy is known to be associated with elevated D-dimers and pro–coagulability, the implications of elevated D-dimers in this clinical context remain unclear.
      • Kline J.A.
      • Williams G.W.
      • Hernandez-Nino J.
      D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed.
      Notably, only one out of the 427 patients in this study was found to have a pulmonary embolism. On admission, this patient's D-dimer value was 16.4 μg/mL, and a small segmental pulmonary embolism was detected on hospital day 7 via CT imaging. The 17-year-old patient had a successful emergent C-section, and both mother and neonate were later discharged.
      • Martinelli I.
      • Ferrazzi E.
      • Ciavarella A.
      • et al.
      Pulmonary embolism in a young pregnant woman with COVID-19.
      Among patients with reported laboratory values, 128 patients presented with lymphopenia and 97 patients presented with neutrophilia, which is consistent with existing data for SARS-CoV-2 infection as reported in the literature.
      • Frater J.L.
      • Zini G.
      • d’Onofrio G.
      • Rogers H.J.
      COVID-19 and the clinical hematology laboratory.
      However, Wei et al. found that the extent of lymphopenia and neutrophilia in the pregnant COVID-19 population tends to be much higher than that of the general population.
      • Wei L.
      • Gao X.
      • Chen S.
      • et al.
      Clinical characteristics and outcomes between pregnant and non-pregnant women with coronavirus disease 2019: a retrospective cohort study.
      Some authors have suggested that these findings may be indicative of an altered immune response in the setting of a hyperinflammatory state, which may in turn coincide with greater risk for severe disease progression. When considering other historical coronavirus epidemics, similar trends of lymphopenia and/or neutrophilia were also observed with both SARS-CoV-1 and Middle East Respiratory Syndrome (MERS).
      • Frater J.L.
      • Zini G.
      • d’Onofrio G.
      • Rogers H.J.
      COVID-19 and the clinical hematology laboratory.
      ,
      • RSM Wong
      • Wu A.
      • To K.F.
      • et al.
      Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis.
      ,
      • Nassar M.S.
      • Bakhrebah M.A.
      • Meo S.A.
      • Alsuabeyl M.S.
      • Zaher W.A.
      Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: epidemiology, pathogenesis and clinical characteristics.
      Of the 298 patients who gave birth during admission, we found an estimated preterm birth rate of 28.0%. A study comparing pregnancy outcomes among SARS-CoV-1, MERS, and SARS-CoV-2 patients previously showed that these three diseases had associated preterm birth rates of 15.03%, 0%, and 41.11%, respectively.
      • Di Mascio D.
      • Khalil A.
      • Saccone G.
      • et al.
      Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis.
      In contrast to these related viral pneumonias, the values reported by Di Mascio et al.
      • Di Mascio D.
      • Khalil A.
      • Saccone G.
      • et al.
      Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis.
      and our study suggest that COVID-19 may lead to higher preterm birth rates when compared to global preterm birth rates of 12% and 9% in underdeveloped and developed countries, respectively. Further investigation is needed to better characterize these risks and associated causalities.
      Lastly, a primary concern when studying viral infections in pregnant patients is that of the potential for vertical transmission. Significant rates of maternal-fetal transmission were not observed with other coronavirus epidemics, including SARS-CoV-1 and MERS.
      • Di Mascio D.
      • Khalil A.
      • Saccone G.
      • et al.
      Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis.
      As more literature regarding COVID-19 becomes available, there is a growing body of evidence to suggest that the risk of vertical transmission with COVID-19 remains similarly negligible.
      • 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.
      We found that 96.8% of patients in our data set showed no signs of vertical transmission at delivery. For the eight cases (3.2%) in which suspected neonatal infection was reported, six were diagnosed by positive RT-PCR. However, as testing was performed on samples collected up to 72 h postpartum, the possibility of extrauterine exposure must be considered. One such example was shown in Mehta et al., a case series that reported delivery of a pair of fraternal twins in which only one of the two neonates tested positive for SARS-CoV-2 by RT-PCR.
      • Mehta H.
      • Ivanovic S.
      • Cronin A.
      • et al.
      Novel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: a case report.
      As vertical transmission to only one of the two neonates in the shared intrauterine environment would seem unlikely, a more plausible explanation is that Twin A may have been infected during the 72-hour postpartum period prior to sample collection. In addition, the remaining two cases of neonatal infection were diagnosed by IgG antibody positivity on samples collected 2 h postpartum. However, as IgG antibodies are known to cross transplacentally, it is also possible that the IgG antibodies detected in the neonates' blood were of maternal origin. This hypothesis was supported by negative results on all subsequent RT-PCR tests in both cases.

      4.1 Study limitations

      There were several factors that limited our study. Firstly, as the findings from this systematic review were aggregated primarily from case reports and case series, we acknowledge a risk of sampling bias in that such reports often tend to skew toward only reporting positive findings. Secondly, a number of the articles included in this systematic review did not adhere to a standardized lexicon to describe the chest CT findings of COVID-19. As a result, many of the reported imaging findings required investigator interpretation for appropriate classification using standard morphologic descriptors. For this reason, we argue in favor of adopting a common lexicon for describing COVID-19-associated features, as described by Salehi et al.
      • Salehi S.
      • Abedi A.
      • Balakrishnan S.
      • Gholamrezanezhad A.
      Coronavirus disease 2019 (COVID-19) imaging reporting and data system (COVID-RADS) and common lexicon: a proposal based on the imaging data of 37 studies.
      Use of a standardized reporting system will improve both patient care and future research by facilitating clear and concise communication when discussing features of COVID-19 pneumonia. Additionally, another limiting factor was the scarcity of published case reports of COVID-19 in pregnant patients, which made it difficult to assemble a larger sample size. Lastly, many articles did not clearly state the radiation dose administered, which may have affected the resolution of images and ability to detect subtle findings.

      5. Conclusion

      Our data from 427 pregnant patients diagnosed with COVID-19 suggest a higher prevalence of consolidation and pleural effusion on chest CT compared to the general adult population. In addition, a lymphopenia/neutrophilia pattern was observed in our study cohort, which is in concordance with data from existing COVID-19 literature. These laboratory abnormalities were similarly reported in patients evaluated during prior SARS-CoV-1 and MERS epidemics. Lastly, despite an increased rate of prematurity as compared to the world preterm birth rate, we do not observe frequent vertical transmission of COVID-19 infection. While our results suggest more advanced presentations than would be otherwise expected for age, further study is needed to more definitively quantify our findings against historical controls.

      CRediT authorship contribution statement

      RSL and DM conducted the initial literature search and screening of articles. RRO and MYCC conducted the subsequent literature search and screening of articles with assistance from NLD and BKKF. RRO and MYCC extracted the quantitative data from each of the selected papers and assessed the quality of each publication. RRO and MYCC drafted the manuscript with support from NLD, BKKF, and AG, who conceived the idea. All authors provided edits on the manuscript prior to submission. RRO and MYCC contributed equally to the work and should be considered as co-first authors.
      The authors declare that they had full access to all of the data in this study and the authors take complete responsibility for the integrity of the data and the accuracy of the data analysis.

      IRB

      None.

      Funding

      None.

      Disclosures

      None.

      Declaration of competing interest

      None.

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