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Disease Severity and Perinatal Outcomes of Pregnant Patients With Coronavirus Disease 2019 (COVID-19)

Disease Severity and Perinatal Outcomes of Pregnant Patients With Coronavirus Disease 2019... Original Research Disease Severity and Perinatal Outcomes of Pregnant Patients With Coronavirus Disease 2019 (COVID-19) Torri D. Metz, MD, MS, Rebecca G. Clifton, PhD, Brenna L. Hughes, MD, Grecio Sandoval, MA, George R. Saade, MD, William A. Grobman, MD, MBA, Tracy A. Manuck, MD, MS, Menachem Miodovnik, MD, Amber Sowles, BSN, RN, Kelly Clark, BSN, RN, Cynthia Gyamfi- Bannerman, MD, MS, Hector Mendez-Figueroa, MD, Harish M. Sehdev, MD, Dwight J. Rouse, MD, Alan T.N. Tita, MD, PhD, Jennifer Bailit, MD, MPH, Maged M. Costantine, MD, Hyagriv N. Simhan, MD, and George A. Macones, MD, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network* OBJECTIVE: To describe coronavirus disease 2019 certified perinatal research staff. We evaluated trends (COVID-19) severity in pregnant patients and evaluate in maternal characteristics and outcomes across COVID- the association between disease severity and perinatal 19 severity classes and associations between severity and outcomes. outcomes by multivariable modeling. METHODS: We conducted an observational cohort RESULTS: A total of 1,219 patients were included: 47% study of all pregnant patients with a singleton gestation asymptomatic, 27% mild, 14% moderate, 8% severe, 4% and a positive test result for severe acute respiratory critical. Overall, 53% were Hispanic; there was no trend syndrome coronavirus 2 (SARS-CoV-2) who delivered at in race–ethnicity distribution by disease severity. Those 1 of 33 U.S. hospitals in 14 states from March 1 to July 31, with more severe illness had older mean age, higher 2020. Disease severity was classified by National Insti- median body mass index, and pre-existing medical co- tutes of Health criteria. Maternal, fetal, and neonatal morbidities. Four maternal deaths (0.3%) were attributed outcomes were abstracted by centrally trained and to COVID-19. Frequency of perinatal death or a positive *A list of other members of the NICHD MFMU Network is available in the Presented at the Society for Maternal-Fetal Medicine’s 41st Annual Pregnancy Appendix 1 online at http://links.lww.com/AOG/C219. Meeting, held virtually, January 25–30, 2021. From the Departments of Obstetrics and Gynecology, University of Utah Health Dr. Rouse, Editor-in-Chief, and Dr. Metz, Associate Editor, Obstetrics, for Sciences Center, Salt Lake City, Utah, University of Texas Medical Branch at Obstetrics & Gynecology, were not involved in the review or decision to Galveston, Galveston, Texas, Northwestern University, Chicago, Illinois, Uni- publish this article. versity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, Each author has confirmed compliance with the journal’s requirements for authorship. Columbia University, New York, New York, University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Houston, Texas, Published online ahead-of-print February 8, 2021. University of Pennsylvania, Philadelphia, Pennsylvania, Brown University, Corresponding author: Torri D. Metz, MD, MS, Department of Obstetrics and Providence, Rhode Island, University of Alabama at Birmingham, Birmingham, Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT; Alabama, MetroHealth Medical Center, Case Western Reserve University, Cleve- email: torri.metz@hsc.utah.edu. land, Ohio, The Ohio State University, Columbus, Ohio, University of Pittsburgh, Financial Disclosure: Pittsburgh, Pennsylvania, and University of Texas at Austin, Austin, Texas; the Torri Metz is the site Principal Investigator (PI) for a Pfizer RSV vaccination study, a George Washington University Biostatistics Center, Washington, DC; and the Novavax RSV vaccination study, and a Gestvision study of the validity of a point-of- Eunice Kennedy Shriver National Institute of Child Health and Human care preeclampsia test. She also receives royalties for two UpToDate topics on vaginal Development, Bethesda, Maryland. birth after cesarean. Brenna Hughes disclosed receiving funds from Merck. Cynthia This work is funded by the Eunice Kennedy Shriver National Institute of Gyamfi-Bannerman disclosed that money was paid to her institution from NICHD/ Child Health and Human Development (UG1 HD087230, UG1 HD027869, NHLBI and AMAG/SMFM. She has received funds from Sera Prognostics as a UG1 HD027915, UG1 HD034208, UG1 HD040500, UG1 HD040485, Medical Advisory Board Member. Alan Tita reports money was paid to his institution UG1 HD053097, UG1 HD040544, UG1 HD040545, UG1 HD040560, from Pfizer. The other authors did not report any potential conflicts of interest. UG1 HD040512, UG1 HD087192, U10 HD036801) and the National Cen- © 2021 by the American College of Obstetricians and Gynecologists. Published by ter for Advancing Translational Sciences (UL1TR001873). The content is solely Wolters Kluwer Health, Inc. All rights reserved. the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ISSN: 0029-7844/21 VOL. 137, NO. 4, APRIL 2021 OBSTETRICS & GYNECOLOGY 571 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. neonatal SARS-CoV-2 test result did not differ by sever- The Eunice Kennedy Shriver National Institute of ity. Adverse perinatal outcomes were more frequent Child Health and Human Development (NICHD) among patients with more severe illness, including 6% Maternal-Fetal Medicine Units (MFMU) Network (95% CI 2–11%) incidence of venous thromboembolism consists of 12 centers with more than 30 separate aca- among those with severe–critical illness compared with demic and community hospitals. Together these sites 0.2% in mild–moderate and 0% in asymptomatic (P,.001 represent the demographic, racial-ethnic and socio- for trend across severity). In adjusted analyses, severe– economic diversity present in the United States. At critical COVID-19 was associated with increased risk of each site, trained research staff have the capacity to cesarean birth (59.6% vs 34.0%, adjusted relative risk identify all pregnant patients with a positive test result [aRR] 1.57, 95% CI 1.30–1.90), hypertensive disorders of for severe acute respiratory syndrome coronavirus 2 pregnancy (40.4% vs 18.8%, aRR 1.61, 95% CI 1.18–2.20), (SARS-CoV-2) delivering there and to perform and preterm birth (41.8% vs 11.9%, aRR 3.53, 95% CI detailed medical record abstraction using a standard- 2.42–5.14) compared with asymptomatic patients. Mild– ized protocol. Therefore, we aimed to describe moderate COVID-19 was not associated with adverse COVID-19 disease severity in a large, diverse cohort perinatal outcomes compared with asymptomatic of pregnant patients. In addition, we aimed to com- patients. pare perinatal outcomes among patients based on dis- CONCLUSION: Compared with pregnant patients with ease severity. We hypothesized that patients with SARS-CoV-2 infection without symptoms, those with more severe COVID-19 would have worse perinatal severe–critical COVID-19, but not those with mild– outcomes. moderate COVID-19, were at increased risk of perinatal complications. METHODS (Obstet Gynecol 2021;137:571–80) This study was an observational cohort of all pregnant DOI: 10.1097/AOG.0000000000004339 patients with a positive SARS-CoV-2 molecular or antigen test result who delivered at 1 of 33 NICHD xisting reports of coronavirus disease 2019 MFMU sites (six community and 27 academic) in 14 E (COVD-19) in pregnant patients are largely lim- states between March 1, 2020, and July 31, 2020. ited to single centers or geographic areas, registries Patients were included if they had a positive test result requiring self-referral or health care practitioner refer- at any point during pregnancy (inpatient or outpa- ral, and meta-analyses of case series in the inpatient tient), and a singleton gestation. Both symptomatic 1–4 setting. A systematic review and meta-analysis of patients and asymptomatic patients were included. cohort studies with pregnant patients found an associ- During the study time period, some of the sites ation between COVID-19 and both preterm birth and performed SARS-CoV-2 testing for all patients admit- neonatal intensive care unit (NICU) admission. ted for delivery regardless of symptoms or known However, available data did not permit examination exposures. Patients with positive antibody testing of other important perinatal outcomes, and the meta- alone were not included. Owing to public health analysis includes some studies in which COVID-19 concern and potential selection bias, data were was diagnosed based on clinical suspicion without collected under a waiver of informed consent with testing. In addition, data from the United States are institutional review board approval at each of the largely derived from those contained in the Morbidity participating institutions. Data were analyzed by an and Mortality Weekly Report, which are administrative independent data coordinating center. data provided by public health departments without Gestational age at the time of the positive SARS- details regarding clinical disease course. CoV-2 test result was calculated based on best Recently Adhikari et al performed a retrospective obstetric estimated date of delivery and the date of cohort study of pregnant patients delivering at a single the first positive SARS-CoV-2 test result. Detailed academic center and found no association between electronic medical record abstraction was performed COVID-19 and a composite adverse perinatal out- by local perinatal research teams at each MFMU site come of preterm birth, preeclampsia with severe fea- after centralized training and certification by the data tures, or cesarean birth. However, 95% of the cohort coordinating center. Data quality checks were per- had asymptomatic or mild disease, and it remains formed on an ongoing basis to ensure high-quality unknown whether perinatal outcomes differ by data across all participating sites. COVID-19 severity. The relationship between Descriptive data regarding maternal COVID-19 COVID-19 and perinatal outcomes among pregnant disease severity were abstracted from the electronic patients in the United States remains largely unknown. medical record, including symptoms, vital signs, 572 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. imaging results, laboratory values, treatments, com- race, were categorized as Hispanic. The “other race” plications, and high-intensity interventions including category includes non-Hispanic Asian, Native Hawai- intubation, dialysis, and extracorporeal membrane ian or Pacific Islander, American Indian/Alaskan oxygenation. Hospitalizations and intensive care unit Native, unknown or more than one race. These cate- (ICU) admissions during pregnancy through 42 days gories were collapsed to make comparisons between postpartum also were enumerated. Self-reported groups with low frequency of patients in the other race symptoms were recorded based on record review categories. In addition, those with severe and critical from the patient encounter at the time of a SARS- illness were grouped together for statistical compari- CoV-2 test that included a duration of onset on or 14 sons, as were those with mild and moderate illness. days before the test or diagnosis date. The Cochran-Armitage trend test for binary variables, Patients were classified as having asymptomatic, score test from multinomial logistic regression for mild, moderate, severe, or critical illness based on multinomial variables, or Jonckheere-Terpstra trend National Institutes of Health guidelines for severity of test for continuous variables were used to assess trends clinical presentation (see Appendix 2, available online in baseline characteristics and perinatal outcomes at http://links.lww.com/AOG/C219). Classification across the severe–critical, mild–moderate, and was based on self-reported symptoms as described asymptomatic categories. above or the patient’s worst clinical status from their Severe–critical COVID-19 and mild–moderate presentation for SARS-CoV-2 testing through deliv- COVID-19 were each compared with asymptomatic ery discharge. patients using multivariable modeling. Multivariable Maternal outcomes included death, ICU admis- modeling was not performed for outcomes with low sion, venous thromboembolism, postpartum hemor- frequencies including maternal death, stillbirth or neo- rhage, hypertensive disorders of pregnancy, and natal death, maternal venous thromboembolism, or cesarean birth. Venous thromboembolism was positive SARS-CoV-2 test results for the neonate. Co- defined as cerebral venous sinus thrombosis, arterial variates for modeling were selected based on clinical thrombosis cerebrovascular accident, pulmonary em- relevance and included maternal age, body mass bolism, or deep venous thrombosis. Postpartum index (BMI, calculated as weight in kilograms divided hemorrhage was defined as estimated blood loss by height in meters squared) at first prenatal visit or (if greater than 1,000 mL. Hypertensive disorders of that was not available) preconceptionally, and major pregnancy were defined according to American Col- medical comorbidity (any of the following: asthma of lege of Obstetricians and Gynecologists criteria for any severity or chronic obstructive pulmonary dis- hemolysis, elevated liver enzymes, and low platelet ease, chronic hypertension, or pregestational count (HELLP) syndrome; eclampsia; preeclampsia diabetes). with or without severe features; gestational hyperten- Models for hypertensive disorders of pregnancy sion; and chronic hypertension with superimposed and preterm birth also included a covariate for preeclampsia. Medical records were reviewed for obstetric history (categorized as no prior pregnancy outpatient visits and re-admissions through 42 days 20 weeks of gestation or longer, history of preterm postpartum for maternal outcomes. birth or hypertensive disorder of pregnancy, or prior Neonatal outcomes included perinatal death, pregnancy without preterm birth or hypertensive positive molecular or antigen SARS-CoV-2 test result disorder of pregnancy). The model for cesarean birth during birth admission, and preterm birth before 37 included history of cesarean birth (categorized as no weeks of gestation. Among live births, additional prior pregnancy 20 weeks of gestation or longer, outcomes included neonatal intermediate care unit history of only vaginal births, or any prior cesarean or NICU admission, birth weight, 5-minute Apgar birth) in addition to the baseline demographic vari- score 3 or less as a marker of adverse neonatal ables above. For continuous outcomes, generalized outcomes, and small-for-gestational-age birth weight linear models were used to estimate the difference of less than the 10th percentile based on the Duryea means and 95% CIs. For categorical outcomes, et al nomogram. Neonates were followed only modified Poisson regression models were used to through the delivery hospitalization. estimate relative risks and 95% CIs. Summary statistics were calculated for baseline A sensitivity analysis was performed in which characteristics. Race and ethnicity data were missing BMI values were imputed based on a abstracted from the medical record and were based generalized linear model and adjusted models were on patient self-report at the time of clinical care. All re-run. The imputation modeled the natural-log scale patients identified as Hispanic ethnicity, regardless of BMI with linear, quadratic, and cubic natural-log scale VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 573 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. BMI at delivery calculated from the most recent among those with severe–critical illness, 18 days (1– pregnancy weight before delivery. For patients with 47) among those with mild–moderate illness, and 1 BMI at delivery and without prenatal (or preconcep- day (0–2) for asymptomatic individuals. Of those who tional) BMI, imputed BMI values were the back- were asymptomatic with a positive SARS-CoV-2 test transformed predicted values based on the model. result, 97% were tested in the context of universal Analyses were performed with SAS 9.4. Adjust- screening at the time of delivery admission. ments were not made for multiple comparisons. The majority of critically ill patients were classi- fied as such owing to respiratory failure (Table 1). RESULTS Overall, the most common patient-reported symp- Of 1,291 pregnant patients with a positive SARS- toms were cough (34%), dyspnea (19%), and myalgias CoV-2 test result over the study time period, 1,219 (19%). Those classified as severe most frequently had (94%) had a singleton gestation and tested positive tachypnea or hypoxia. Although the majority of during pregnancy, and were included in the analysis patients with severe and critical illness had abnormal (Fig. 1). Of these, 579 (47%) were asymptomatic, 326 results on chest radiologic imaging (chest X-ray or (27%) had mild illness, 173 (14%) had moderate ill- computed tomography scan), only a small proportion ness, 98 (8%) had severe illness, and 43 (4%) had had more than 50% lung involvement (1% and 5%, respectively). critical illness (Fig. 1). Among the patients with Tests of trend were significant for differences in severe–critical illness, 11% were transported from another health care facility. age, median BMI, and insurance status across disease The median (interquartile range) gestational age severity (Table 2). The majority (53%) of enrolled at the time of first positive SARS-CoV-2 test result patients were of Hispanic ethnicity; however, there was 37.7 weeks of gestation (33.7–39.1). The majority was no trend in race–ethnicity distribution by sever- of SARS-CoV-2 tests were performed in the inpatient ity. Tests of trend were significant for differences in setting (67%). The number of days from the first pos- frequency of medical comorbidities including asthma itive SARS-CoV-2 test result to delivery varied by or chronic obstructive pulmonary disease, chronic disease severity, with a median of 4 days (1–28) hypertension, prepregnancy diabetes, chronic liver Fig. 1. Study cohort. First positive test result (molecular or antigen) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); coronavirus disease 2019 (COVID-19) classification based on data through delivery hospitalization. *Respiratory failure is use of any of the following: extracorporeal membrane oxygenation, continuous positive airway pressure, bi-level positive airway pressure, ventilation. Multiple organ dysfunction or failure is two or more of the following: cardiac arrest, impaired liver function, renal insufficiency (serum creatinine greater than 1.10 mg/dL), renal failure requiring dialysis, encephalopathy, any need for pressor support, thrombocytopenia (platelets less than 100,000). Other symptoms include fever, cough, sore throat, fatigue, muscle pain, chills, back pain, nausea, vomiting, joint pain, nasal stuffiness, conjunctivitis, confusion, loss of smell or taste, diarrhea, or other. MFMU, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units. Metz. COVID-19 Severity and Perinatal Outcomes. Obstet Gynecol 2021. 574 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 1. Coronavirus Disease 2019 (COVID-19) Disease Severity Classification for Study Cohort* Critical Severe Moderate Mild Asymptomatic Data Through Delivery Hospitalization (n543) (n598) (n5173) (n5326) (n5579) Respiratory failure 29 (67) Septic shock 8 (19) Multiple organ dysfunction or failure 26 (61) Death due to COVID-19 4 (9) Respiratory frequency greater than 30 breaths/min 29 (67) 70 (71) SpO less than 94% with O support 27 (63) 59 (60) 2 2 PaO or FiO less than 300 mm Hg 18 (42) 4 (4) 2 2 High-flow nasal cannula 1 (2) 6 (6) Lung infiltrates greater than 50% on CT or chest X-ray 2 (5) 1 (1) Abnormal chest imaging results (lung infiltrates less 31 (72) 51 (52) 47 (27.2) than or equal to 50%) Documentation of self-reported dyspnea 24 (56) 55 (56) 151 (87.3) Any other self-reported symptoms (excluding dyspnea) 35 (81) 84 (86) 171 (98.8) 326 (100) Cough 28 (65) 63 (64) 131 (75.7) 192 (58.9) Myalgia or body aches 15 (35) 40 (41) 76 (43.9) 101 (31.0) Fever 18 (42) 41 (42) 63 (36.4) 92 (28.2) Nasal stuffiness or rhinorrhea 3 (7) 24 (25) 65 (37.6) 111 (34.0) Headache 9 (21) 21 (21) 62 (35.8) 96 (29.4) Other symptoms 18 (42) 30 (31) 67 (38.7) 61 (18.7) Chills (shaking) 16 (37) 38 (39) 49 (28.3) 54 (16.6) Anosmia or loss of smell 8 (19) 12 (12) 43 (24.9) 78 (23.9) Fatigue 13 (30) 25 (26) 49 (28.3) 46 (14.1) Sore throat 9 (21) 20 (20) 39 (22.5) 63 (19.3) Nausea or vomiting 8 (19) 28 (29) 46 (26.6) 47 (14.4) Ageusia or loss of taste 6 (14) 12 (12) 42 (24.3) 67 (20.6) Back or joint pain 7 (16) 18 (18) 20 (11.6) 20 (6.1) Diarrhea 5 (12) 11 (11) 21 (12.1) 26 (8.0) Confusion 3 (7) 0 0 2 (0.6) Conjunctivitis 0 2 (2) 2 (1.2) 0 No symptoms 579 (100) COVID-19, coronavirus disease 2019; CT, computed tomography. Data are n (%). Many patients met multiple criteria for disease severity category. * First positive SARS-CoV-2 test result (nucleic acid or antigen) during pregnancy; COVID-19 classification based on available data through delivery hospitalization. Respiratory failure is use of any of the following: extracorporeal membrane oxygenation, continuous positive airway pressure, bi-level positive airway pressure, ventilation. Multiple organ dysfunction or failure is two or more of the following: cardiac arrest, impaired liver function, renal insufficiency (serum creatinine greater than 1.10 mg/dL), renal failure requiring dialysis, encephalopathy, any need for pressor support, thrombocytopenia (platelets less than 100,000). disease, and seizure disorder across disease severity. frequency of neonatal or fetal death by disease sever- Illness severity was not related to ABO blood type or ity is described in Table 3. presence of Rhesus factor (Table 2). A thromboembolic event occurred in eight Vital sign and laboratory findings by COVID-19 patients (6%, 95% CI 2–11%) in the severe–critical severity are described in Appendix 3, available online group; all of these events were deep venous throm- at http://links.lww.com/AOG/C219. Maternal and boses or pulmonary emboli. In comparison, there was perinatal deaths are presented in Table 3. Four mater- one (0.2%) thromboembolism in the mild–moderate nal deaths (0.3%) were thought to be due to COVID- group and none (0%) in the asymptomatic group 19; autopsies were not performed in all cases. Two (P,.001 for trend across severity) (Table 3). Of those other maternal deaths occurred during the study time with a venous thromboembolism, five received pro- period and were not related to infection; both had phylactic anticoagulation before the event, all in the severe COVID-19 before dying of other causes. The severe–critical group. VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 575 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 2. Baseline Demographic and Clinical Characteristics Disease Severity Critical–Severe Moderate–Mild Asymptomatic P for Characteristic (n5141) (n5499) (n5579) Trend* Age (y) 3066.2 2966.3 2866.3 .006 BMI (kg/m ) 32.3 (27.1–37.5) 29.0 (25.2–34.3) 28.3 (24.6–33.0) ,.001 30 or higher 66 (58.4) 202 (44.7) 198 (40.0) ,.001 40 or higher 20 (17.7) 40 (8.9) 35 (7.1) .002 Race–ethnicity .77 Non-Hispanic Black 30 (21.3) 122 (24.4) 123 (21.2) Non-Hispanic White 13 (9.2) 88 (17.6) 80 (13.8) Hispanic 81 (57.4) 246 (49.3) 324 (56.0) Other, unknown, or more than 1 race 17 (12.1) 43 (8.6) 52 (9.0) No prior pregnancy 20 wk or longer 48 (34.0) 153 (30.7) 187 (32.3) .98 Previous preterm birth (20 to less than 37 13 (9.2) 49 (9.8) 61 (10.6) .59 wk) Previous cesarean birth 33 (23.4) 112 (22.4) 122 (21.1) .49 Previous hypertensive disorder of 16 (11.3) 69 (13.8) 45 (7.8) .02 pregnancy Employed 61 (61.6) 219 (55.7) 194 (50.3) .03 Private insurance 46 (33.6) 160 (32.3) 124 (21.9) ,.001 Smoked during this pregnancy 5 (3.5) 18 (3.6) 27 (4.7) .39 Any substance use during this pregnancy 6 (4.3) 32 (6.4) 21 (3.6) .22 Blood type .16 A 45 (31.9) 161 (32.3) 154 (26.6) B 17 (12.1) 67 (13.5) 64 (11.1) AB 3 (2.1) 19 (3.8) 20 (3.5) O 76 (53.9) 251 (50.4) 340 (58.8) Rh-positive 133 (94.3) 466 (93.6) 541 (93.6) .81 Immunocompromising condition 3 (2.1) 11 (2.2) 4 (0.7) .06 Asthma or chronic obstructive pulmonary 29 (20.6) 85 (17.0) 51 (8.8) ,.001 disease Pregestational diabetes 14 (9.9) 18 (3.6) 17 (2.9) .002 Thrombophilia 0 4 (0.8) 3 (0.5) .79 Chronic hypertension 16 (11.3) 35 (7.0) 29 (5.0) .007 Chronic cardiovascular disease 2 (1.4) 9 (1.8) 3 (0.5) .11 Chronic renal disease 1 (0.7) 2 (0.4) 0 .08 Chronic liver disease 3 (2.1) 2 (0.4) 1 (0.2) .01 Thyroid disease 10 (7.1) 22 (4.4) 22 (3.8) .13 Neurocognitive disorder 2 (1.4) 23 (4.6) 10 (1.7) .25 Neuromuscular disorder 2 (1.4) 1 (0.2) 1 (0.2) .07 Seizure disorder 5 (3.5) 5 (1.0) 4 (0.7) .02 Inflammatory bowel disease 1 (0.7) 2 (0.4) 0 .08 BMI, body mass index. Data are mean6SD, median (interquartile range), or n (%) unless otherwise specified. Number of missing values: BMI (n5159), previous pregnancy (n51), employment status (n5341), insurance status (n520), blood type (n52), Rh factor (n52). * P-value based on Cochran-Armitage trend test for binary variables, score test from multinomial logistic regression for multinomial variables, or Jonckheere-Terpstra trend test for continuous variables. All patients identified as Hispanic ethnicity, regardless of race, were categorized as Hispanic. Other race includes non-Hispanic Asian, Native Hawaiian/Pacific Islander, American Indian/Alaskan Native, unknown, and more than one race. Overall, 6% of the cohort had an antepartum COVID-19. Among the patients initially classified as admission for treatment of COVID-19 separate from asymptomatic during the delivery hospitalization, one the delivery hospitalization. Fifty-nine (5%) were admit- had a hospital readmission with ICU care for COVID- ted to the ICU either during the pregnancy or within 42 19 after delivery discharge but before 42 days postpar- days postpartum (Table 3). The majority of the ICU tum. Other ICU admissions in asymptomatic patients admissions (45/59, 76%) were for an indication of were for indications unrelated to COVID-19. 576 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 3. Perinatal Outcomes by Coronavirus Disease 2019 (COVID-19) Severity Critical–Severe (n5141) Moderate–Mild (n5499) Asymptomatic RR aRR* RR aRR* (ref) P for Outcome (95% CI) (95% CI) (95% CI) (95% CI) (n5579) Trend Maternal death 6 (4.3) 0 0 ,.001 Venous thromboe- 8 (5.7) 1 (0.2) 0 ,.001 mbolism Maternal ICU 50 (35.5) 68.4 (21.7–216) 57.5 (17.8– 6 (1.2) 2.32 (0.58– 2.07 (0.51– 3 (0.5) ,.001 admission 186.3) 9.23) 8.34) Cesarean birth 84 (59.6) 1.75 (1.47–2.09) 1.57 (1.30–1.90) 169 (33.9) 1.00 (0.84– 0.94 (0.81– 197 (34.0) ,.001 1.18) 1.09) Postpartum 21 (14.9) 2.05 (1.26–3.35) 2.02 (1.18–3.45) 45 (9.0) 1.24 (0.83– 1.21 (0.78– 42 (7.3) .008 hemorrhage 1.86) 1.87) Hypertensive 57 (40.4) 2.15 (1.65–2.79) 1.61 (1.18–2.20) 119 (23.8) 1.27 (1.01– 1.24 (0.98– 109 (18.8) ,.001 disorders of 1.60) 1.58) pregnancy Fetal or neonatal 6 (4.3) 11 (2.2) 11 (1.9) .15 death Fetal loss at less36 4 than 20 wk Fetal loss at 2014 5 wk or later Neonatal death 2 1 2 Preterm birth (less 59 (41.8) 3.51 (2.61–4.72) 3.53 (2.42–5.14) 76 (15.2) 1.28 (0.94– 1.36 (0.97– 69 (11.9) ,.001 than 37 wk) 1.73) 1.91) Spontaneous 10 (16.9) 30 (39.5) 35 (50.7) Indicated 49 (83.1) 46 (60.5) 34 (49.3) Live birth 137 489 570 SGA (less than the 11 (8.0) 0.81 (0.44–1.51) 1.22 (0.63–2.37) 59 (12.2) 1.23 (0.87– 1.48 (1.02– 56 (9.9) .93 10th 1.74) 2.16) percentile) Birth weight (g) 2,8416726.1 2364 (2479 to 2385 (2510 to 3,1746600.1 232 (2106 261 (2138 3,2056603.9 ,.001 ¶ ¶ ¶ ¶ 2249) 2261) to 43) to 15) NICU admission 69 (50.4) 3.15 (2.45–4.06) 3.12 (2.32–4.20) 94 (19.2) 1.20 (0.93– 1.24 (0.93– 91 (16.0) ,.001 1.56) 1.66) ref, referent; RR, relative risk; aRR, adjusted relative risk; ICU, intensive care unit; SGA, small for gestational age; NICU, neonatal intensive care unit. Data are n (%) or mean6SD unless otherwise specified. Number of missing values: size for gestational age (n56). * All models adjusted for maternal age, body mass index, and major medical comorbidity; hypertensive disorders of pregnancy and preterm birth also adjusted for obstetric history of preterm birth or hypertensive disorder of pregnancy; cesarean birth also adjusted for history of cesarean birth. Cochran-Armitage trend test for binary variables or Jonckheere-Terpstra trend test for continuous variables. Venous thromboembolism defined as cerebral venous sinus thrombosis, arterial thrombosis cerebrovascular accident, pulmonary embolism, deep venous thrombosis. Postpartum hemorrhage defined as estimated blood loss greater than 1,000 mL. Hypertensive disorders of pregnancy defined as hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; eclampsia; preeclampsia with or without severe features; gestational hypertension; and chronic hypertension with superimposed preeclampsia according to American College of Obstetricians and Gynecologists definitions. Difference in means. Neonatal intermediate or intensive care unit. Rates for cesarean birth, postpartum hemorrhage, (aRR 3.53, 95% CI 2.42–5.14) compared with asymp- hypertensive disorders of pregnancy and preterm tomatic patients. In a sensitivity analysis in which BMI birth were 36.9%, 8.9%, 23.4% and 16.7%, respec- was imputed for those with missing values (n5159, tively. Adverse maternal and neonatal outcomes were 13%), the adjusted association between severe– more frequent in patients with severe COVID-19 critical and postpartum hemorrhage was no longer illness (Table 3). In adjusted analyses, severe–critical significant (aRR 1.68, 95% CI 1.00–2.84). COVID-19 was associated with a higher risk of cesar- Preterm births among patients with severe– ean birth (adjusted relative risk [aRR] 1.57, 95% CI critical illness were indicated (rather than spontane- 1.30–1.90), postpartum hemorrhage (aRR 2.02, 95% ous) in 83% of cases compared with 61% in patients CI 1.18–3.45), hypertensive disorders of pregnancy with mild–moderate illness and 49% in patients who (aRR 1.61, 95% CI 1.18–2.20), and preterm birth were symptomatic (P,.001 for trend across severity VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 577 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. for indicated delivery among preterm births). Of those associated with higher risk of NICU admission and induced preterm (n567), COVID-19 was the primary lower birth weight compared with neonates of asymp- indication for induction of labor in 3%. The most tomatic patients. common indications for induction among the preterm Our findings regarding preterm birth and NICU births were hypertensive disorders of pregnancy admission are consistent with a previous report. (33%), stillbirth (16%), and preterm prelabor rupture However, in our cohort, the increased risk of preterm of membranes (13%). Of those who underwent pre- birth was driven by indicated, rather than spontane- term cesarean birth (n5106), COVID-19 was the pri- ous, preterm birth. Our work also expands what is mary indication for cesarean in 22%. The other known about perinatal outcomes in patients with common indications for cesarean among those with COVID-19 by demonstrating that severe or critical preterm births were nonreassuring fetal status (29%), illness is associated with a number of other adverse hypertensive disorders of pregnancy (15%), and perinatal outcomes for both the patient and the abnormal presentation (11%). neonate. Severe–critical maternal illness was associated We observed a 6% VTE rate in the severe–critical with NICU admission and lower birth weight. Mild– group. National Institutes of Health treatment guide- moderate maternal illness was marginally associated lines recommend prophylactic anticoagulation in with small-for-gestational-age birth weight, although pregnant hospitalized patients with COVID-19. this association was no longer significant when BMI Nonetheless, our data are consistent with those in was imputed for those with missing values. Among nonpregnant patients in that critically ill patients with patients who were induced or had cesarean birth, COVID-19 have a high rate of VTE even when COVID-19 was the indication for induction or cesar- receiving prophylactic anticoagulation. Ongoing ean in 32 of 112 (29%) of the patients with severe– randomized controlled trials are evaluating whether critical illness, 12 of 330 (4%) with mild–moderate therapeutic anticoagulation reduces risk of VTE when illness, and 16 of 352 (5%) who were asymptomatic. compared with prophylactic anticoagulation. Further In total, 1.0% (95% CI 0.5–1.8%) of neonates study is also needed to determine the need for anti- tested positive for SARS-CoV-2 before discharge. coagulation in the setting of less severe COVID-19 The rate of positive neonatal SARS-CoV-2 test results illness during pregnancy as there was an isolated among live births was 1.5% in the severe–critical venous thromboembolic event in the mild–moderate group, 0.6% in the mild–moderate group, and 1.2% group (1 in 499). in the asymptomatic group. The percentage of neo- The rate of a positive neonatal SARS-CoV-2 test nates with a 5-minute Apgar score of 3 or less was result was approximately 1% across sites. The major- 2.9% in the severe–critical, 0.2% in the mild– ity of these neonates were breastfed or breast and moderate, and 0.7% in the asymptomatic group. The bottle fed. We were limited in our capacity to evaluate majority (900/1,190 with available data, 76%) of for vertical transmission because only clinical testing neonates in the cohort were breastfed or breast and was available, and, in many cases, this does not bottle fed. Among patients in whom an offer of include serial testing of the neonate and evaluation maternal–neonatal separation owing to SARS-CoV-2 of the placenta as required to confirm vertical trans- infection was documented (n5448, 37%), 312 were mission rather than horizontal transmission after actually separated (26% of total population): 59 of birth. Nonetheless, despite a majority of neonates 64 (92%) with severe–critical illness, 77 of 126 (61%) receiving at least some breastfeeding, positive viral with mild–moderate illness, and 176 of 258 (68%) who testing in the neonates was infrequent. were in the asymptomatic group. Initial Morbidity and Mortality Weekly Report data demonstrated an increased risk for hospitalization DISCUSSION among pregnant patients compared with females of We found that 12% of pregnant patients with reproductive age who were not pregnant; however, COVID-19 had severe or critical illness. Patients with it was not possible to delineate whether the patient severe or critical COVID-19 are at risk for a number was simply admitted for delivery (rather than of perinatal complications including cesarean birth, COVID-19 complications). Our data indicate that, hypertensive disorders of pregnancy, and preterm overall, 6% of pregnant patients who tested positive birth. Those with severe or critical illness also had for SARS-CoV-2 had a hospital admission for increased frequency of venous thromboembolism COVID-19 separate from their delivery hospitaliza- compared with those with less severe illness. In tion. Although this is similar to the 5.8% hospitaliza- addition, severe or critical maternal illness was tion rate published by the Centers for Disease Control 578 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. and Prevention for nonpregnant reproductive-age be interpreted in the context of overlapping signs (eg females, direct comparisons cannot be made given hypertension and lab abnormalities) and symptoms differences in sampling strategy. In addition, patients (eg headache) between preeclampsia with severe with critical illness may have required delivery to features and severe or critical COVID-19; however, improve maternal status during what was initially a standard American College of Obstetricians and COVID-19 hospitalization. Gynecologists’ diagnostic criteria were used for this Centers for Disease Control and Prevention data endpoint to minimize subjectivity. In addition, owing demonstrate an increased risk of death from COVID- to the clinical importance and descriptive nature of 19 and ICU admission among pregnant patients com- the data, analyses were not adjusted for multiple com- pared with nonpregnant patients. Recent hospital- parisons; therefore, some findings could be attributed level administrative data also demonstrate increased to chance. Finally, treatment for COVID-19 was rap- risks of both of these outcomes among patients with idly evolving during the study period, and the effect of COVID-19 compared with those without COVID-19. current treatments on outcomes could not be Our maternal death rate was 0.3% (3/1,000 patients evaluated. with COVID-19), and the ICU admission rate was Strengths of this study include the standardized 4.8% (48/1,000). Both of these rates are higher than collection methods of detailed medical record abstrac- those previously published. A small proportion of the tion by trained and certified perinatal research staff. increase may reflect transports requiring critical care The study included 33 demographically and socio- from other facilities to MFMU tertiary care centers. economically diverse sites, which makes these data However, transports only comprised 11% of the more generalizable than single-center data. In addi- severe–critical study population. Therefore, the high- tion, the size of the study population afforded by er rates may also reflect increased ascertainment of multiple sites allowed for a larger sample to evaluate these outcomes through manual medical record differences in outcomes by disease severity. We abstraction rather than relying on administrative data. included patients with positive test results in both Consistent with prior studies, risk factors for the inpatient and outpatient setting, which expands severe or critical COVID-19 included older age, knowledge related to COVID-19 in pregnancy, as the increased BMI, and underlying medical comorbidities results are not biased by only including inpatients. such as asthma, chronic hypertension, and pregesta- These results suggest that pregnant patients with tional diabetes. The majority of pregnant patients with higher levels of COVID-19 severity are at higher risk COVID-19 in our cohort were of Hispanic ethnicity of perinatal complications. Clinicians should be aware (53%); however, there was no trend in COVID-19 of these risks and consider strategies to mitigate severity based on race–ethnicity. We found a higher complications when possible. frequency of current employment and private insur- ance among those with higher disease severity, which REFERENCES may in part reflect transport of patients with higher 1. Khoury R, Bernstein PS, Debolt C, Stone J, Sutton DM, Simp- son LL, et al. Characteristics and outcomes of 241 births to illness severity to tertiary care centers included in the women with severe acute respiratory syndrome coronavirus 2 MFMU. (SARS-CoV-2) infection at five New York City medical centers. Limitations of this analysis include the fact that Obstet Gynecol 2020;136:273–82. doi: 10.1097/AOG. not all sites were performing universal screening for 0000000000004025 SARS-CoV-2 infection during the entire study period. 2. Griffin I, Benarba F, Peters C, Oyelese Y, Murphy T, Contreras D, et al. 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Abstract

Original Research Disease Severity and Perinatal Outcomes of Pregnant Patients With Coronavirus Disease 2019 (COVID-19) Torri D. Metz, MD, MS, Rebecca G. Clifton, PhD, Brenna L. Hughes, MD, Grecio Sandoval, MA, George R. Saade, MD, William A. Grobman, MD, MBA, Tracy A. Manuck, MD, MS, Menachem Miodovnik, MD, Amber Sowles, BSN, RN, Kelly Clark, BSN, RN, Cynthia Gyamfi- Bannerman, MD, MS, Hector Mendez-Figueroa, MD, Harish M. Sehdev, MD, Dwight J. Rouse, MD, Alan T.N. Tita, MD, PhD, Jennifer Bailit, MD, MPH, Maged M. Costantine, MD, Hyagriv N. Simhan, MD, and George A. Macones, MD, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network* OBJECTIVE: To describe coronavirus disease 2019 certified perinatal research staff. We evaluated trends (COVID-19) severity in pregnant patients and evaluate in maternal characteristics and outcomes across COVID- the association between disease severity and perinatal 19 severity classes and associations between severity and outcomes. outcomes by multivariable modeling. METHODS: We conducted an observational cohort RESULTS: A total of 1,219 patients were included: 47% study of all pregnant patients with a singleton gestation asymptomatic, 27% mild, 14% moderate, 8% severe, 4% and a positive test result for severe acute respiratory critical. Overall, 53% were Hispanic; there was no trend syndrome coronavirus 2 (SARS-CoV-2) who delivered at in race–ethnicity distribution by disease severity. Those 1 of 33 U.S. hospitals in 14 states from March 1 to July 31, with more severe illness had older mean age, higher 2020. Disease severity was classified by National Insti- median body mass index, and pre-existing medical co- tutes of Health criteria. Maternal, fetal, and neonatal morbidities. Four maternal deaths (0.3%) were attributed outcomes were abstracted by centrally trained and to COVID-19. Frequency of perinatal death or a positive *A list of other members of the NICHD MFMU Network is available in the Presented at the Society for Maternal-Fetal Medicine’s 41st Annual Pregnancy Appendix 1 online at http://links.lww.com/AOG/C219. Meeting, held virtually, January 25–30, 2021. From the Departments of Obstetrics and Gynecology, University of Utah Health Dr. Rouse, Editor-in-Chief, and Dr. Metz, Associate Editor, Obstetrics, for Sciences Center, Salt Lake City, Utah, University of Texas Medical Branch at Obstetrics & Gynecology, were not involved in the review or decision to Galveston, Galveston, Texas, Northwestern University, Chicago, Illinois, Uni- publish this article. versity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, Each author has confirmed compliance with the journal’s requirements for authorship. Columbia University, New York, New York, University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Houston, Texas, Published online ahead-of-print February 8, 2021. University of Pennsylvania, Philadelphia, Pennsylvania, Brown University, Corresponding author: Torri D. Metz, MD, MS, Department of Obstetrics and Providence, Rhode Island, University of Alabama at Birmingham, Birmingham, Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT; Alabama, MetroHealth Medical Center, Case Western Reserve University, Cleve- email: torri.metz@hsc.utah.edu. land, Ohio, The Ohio State University, Columbus, Ohio, University of Pittsburgh, Financial Disclosure: Pittsburgh, Pennsylvania, and University of Texas at Austin, Austin, Texas; the Torri Metz is the site Principal Investigator (PI) for a Pfizer RSV vaccination study, a George Washington University Biostatistics Center, Washington, DC; and the Novavax RSV vaccination study, and a Gestvision study of the validity of a point-of- Eunice Kennedy Shriver National Institute of Child Health and Human care preeclampsia test. She also receives royalties for two UpToDate topics on vaginal Development, Bethesda, Maryland. birth after cesarean. Brenna Hughes disclosed receiving funds from Merck. Cynthia This work is funded by the Eunice Kennedy Shriver National Institute of Gyamfi-Bannerman disclosed that money was paid to her institution from NICHD/ Child Health and Human Development (UG1 HD087230, UG1 HD027869, NHLBI and AMAG/SMFM. She has received funds from Sera Prognostics as a UG1 HD027915, UG1 HD034208, UG1 HD040500, UG1 HD040485, Medical Advisory Board Member. Alan Tita reports money was paid to his institution UG1 HD053097, UG1 HD040544, UG1 HD040545, UG1 HD040560, from Pfizer. The other authors did not report any potential conflicts of interest. UG1 HD040512, UG1 HD087192, U10 HD036801) and the National Cen- © 2021 by the American College of Obstetricians and Gynecologists. Published by ter for Advancing Translational Sciences (UL1TR001873). The content is solely Wolters Kluwer Health, Inc. All rights reserved. the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ISSN: 0029-7844/21 VOL. 137, NO. 4, APRIL 2021 OBSTETRICS & GYNECOLOGY 571 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. neonatal SARS-CoV-2 test result did not differ by sever- The Eunice Kennedy Shriver National Institute of ity. Adverse perinatal outcomes were more frequent Child Health and Human Development (NICHD) among patients with more severe illness, including 6% Maternal-Fetal Medicine Units (MFMU) Network (95% CI 2–11%) incidence of venous thromboembolism consists of 12 centers with more than 30 separate aca- among those with severe–critical illness compared with demic and community hospitals. Together these sites 0.2% in mild–moderate and 0% in asymptomatic (P,.001 represent the demographic, racial-ethnic and socio- for trend across severity). In adjusted analyses, severe– economic diversity present in the United States. At critical COVID-19 was associated with increased risk of each site, trained research staff have the capacity to cesarean birth (59.6% vs 34.0%, adjusted relative risk identify all pregnant patients with a positive test result [aRR] 1.57, 95% CI 1.30–1.90), hypertensive disorders of for severe acute respiratory syndrome coronavirus 2 pregnancy (40.4% vs 18.8%, aRR 1.61, 95% CI 1.18–2.20), (SARS-CoV-2) delivering there and to perform and preterm birth (41.8% vs 11.9%, aRR 3.53, 95% CI detailed medical record abstraction using a standard- 2.42–5.14) compared with asymptomatic patients. Mild– ized protocol. Therefore, we aimed to describe moderate COVID-19 was not associated with adverse COVID-19 disease severity in a large, diverse cohort perinatal outcomes compared with asymptomatic of pregnant patients. In addition, we aimed to com- patients. pare perinatal outcomes among patients based on dis- CONCLUSION: Compared with pregnant patients with ease severity. We hypothesized that patients with SARS-CoV-2 infection without symptoms, those with more severe COVID-19 would have worse perinatal severe–critical COVID-19, but not those with mild– outcomes. moderate COVID-19, were at increased risk of perinatal complications. METHODS (Obstet Gynecol 2021;137:571–80) This study was an observational cohort of all pregnant DOI: 10.1097/AOG.0000000000004339 patients with a positive SARS-CoV-2 molecular or antigen test result who delivered at 1 of 33 NICHD xisting reports of coronavirus disease 2019 MFMU sites (six community and 27 academic) in 14 E (COVD-19) in pregnant patients are largely lim- states between March 1, 2020, and July 31, 2020. ited to single centers or geographic areas, registries Patients were included if they had a positive test result requiring self-referral or health care practitioner refer- at any point during pregnancy (inpatient or outpa- ral, and meta-analyses of case series in the inpatient tient), and a singleton gestation. Both symptomatic 1–4 setting. A systematic review and meta-analysis of patients and asymptomatic patients were included. cohort studies with pregnant patients found an associ- During the study time period, some of the sites ation between COVID-19 and both preterm birth and performed SARS-CoV-2 testing for all patients admit- neonatal intensive care unit (NICU) admission. ted for delivery regardless of symptoms or known However, available data did not permit examination exposures. Patients with positive antibody testing of other important perinatal outcomes, and the meta- alone were not included. Owing to public health analysis includes some studies in which COVID-19 concern and potential selection bias, data were was diagnosed based on clinical suspicion without collected under a waiver of informed consent with testing. In addition, data from the United States are institutional review board approval at each of the largely derived from those contained in the Morbidity participating institutions. Data were analyzed by an and Mortality Weekly Report, which are administrative independent data coordinating center. data provided by public health departments without Gestational age at the time of the positive SARS- details regarding clinical disease course. CoV-2 test result was calculated based on best Recently Adhikari et al performed a retrospective obstetric estimated date of delivery and the date of cohort study of pregnant patients delivering at a single the first positive SARS-CoV-2 test result. Detailed academic center and found no association between electronic medical record abstraction was performed COVID-19 and a composite adverse perinatal out- by local perinatal research teams at each MFMU site come of preterm birth, preeclampsia with severe fea- after centralized training and certification by the data tures, or cesarean birth. However, 95% of the cohort coordinating center. Data quality checks were per- had asymptomatic or mild disease, and it remains formed on an ongoing basis to ensure high-quality unknown whether perinatal outcomes differ by data across all participating sites. COVID-19 severity. The relationship between Descriptive data regarding maternal COVID-19 COVID-19 and perinatal outcomes among pregnant disease severity were abstracted from the electronic patients in the United States remains largely unknown. medical record, including symptoms, vital signs, 572 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. imaging results, laboratory values, treatments, com- race, were categorized as Hispanic. The “other race” plications, and high-intensity interventions including category includes non-Hispanic Asian, Native Hawai- intubation, dialysis, and extracorporeal membrane ian or Pacific Islander, American Indian/Alaskan oxygenation. Hospitalizations and intensive care unit Native, unknown or more than one race. These cate- (ICU) admissions during pregnancy through 42 days gories were collapsed to make comparisons between postpartum also were enumerated. Self-reported groups with low frequency of patients in the other race symptoms were recorded based on record review categories. In addition, those with severe and critical from the patient encounter at the time of a SARS- illness were grouped together for statistical compari- CoV-2 test that included a duration of onset on or 14 sons, as were those with mild and moderate illness. days before the test or diagnosis date. The Cochran-Armitage trend test for binary variables, Patients were classified as having asymptomatic, score test from multinomial logistic regression for mild, moderate, severe, or critical illness based on multinomial variables, or Jonckheere-Terpstra trend National Institutes of Health guidelines for severity of test for continuous variables were used to assess trends clinical presentation (see Appendix 2, available online in baseline characteristics and perinatal outcomes at http://links.lww.com/AOG/C219). Classification across the severe–critical, mild–moderate, and was based on self-reported symptoms as described asymptomatic categories. above or the patient’s worst clinical status from their Severe–critical COVID-19 and mild–moderate presentation for SARS-CoV-2 testing through deliv- COVID-19 were each compared with asymptomatic ery discharge. patients using multivariable modeling. Multivariable Maternal outcomes included death, ICU admis- modeling was not performed for outcomes with low sion, venous thromboembolism, postpartum hemor- frequencies including maternal death, stillbirth or neo- rhage, hypertensive disorders of pregnancy, and natal death, maternal venous thromboembolism, or cesarean birth. Venous thromboembolism was positive SARS-CoV-2 test results for the neonate. Co- defined as cerebral venous sinus thrombosis, arterial variates for modeling were selected based on clinical thrombosis cerebrovascular accident, pulmonary em- relevance and included maternal age, body mass bolism, or deep venous thrombosis. Postpartum index (BMI, calculated as weight in kilograms divided hemorrhage was defined as estimated blood loss by height in meters squared) at first prenatal visit or (if greater than 1,000 mL. Hypertensive disorders of that was not available) preconceptionally, and major pregnancy were defined according to American Col- medical comorbidity (any of the following: asthma of lege of Obstetricians and Gynecologists criteria for any severity or chronic obstructive pulmonary dis- hemolysis, elevated liver enzymes, and low platelet ease, chronic hypertension, or pregestational count (HELLP) syndrome; eclampsia; preeclampsia diabetes). with or without severe features; gestational hyperten- Models for hypertensive disorders of pregnancy sion; and chronic hypertension with superimposed and preterm birth also included a covariate for preeclampsia. Medical records were reviewed for obstetric history (categorized as no prior pregnancy outpatient visits and re-admissions through 42 days 20 weeks of gestation or longer, history of preterm postpartum for maternal outcomes. birth or hypertensive disorder of pregnancy, or prior Neonatal outcomes included perinatal death, pregnancy without preterm birth or hypertensive positive molecular or antigen SARS-CoV-2 test result disorder of pregnancy). The model for cesarean birth during birth admission, and preterm birth before 37 included history of cesarean birth (categorized as no weeks of gestation. Among live births, additional prior pregnancy 20 weeks of gestation or longer, outcomes included neonatal intermediate care unit history of only vaginal births, or any prior cesarean or NICU admission, birth weight, 5-minute Apgar birth) in addition to the baseline demographic vari- score 3 or less as a marker of adverse neonatal ables above. For continuous outcomes, generalized outcomes, and small-for-gestational-age birth weight linear models were used to estimate the difference of less than the 10th percentile based on the Duryea means and 95% CIs. For categorical outcomes, et al nomogram. Neonates were followed only modified Poisson regression models were used to through the delivery hospitalization. estimate relative risks and 95% CIs. Summary statistics were calculated for baseline A sensitivity analysis was performed in which characteristics. Race and ethnicity data were missing BMI values were imputed based on a abstracted from the medical record and were based generalized linear model and adjusted models were on patient self-report at the time of clinical care. All re-run. The imputation modeled the natural-log scale patients identified as Hispanic ethnicity, regardless of BMI with linear, quadratic, and cubic natural-log scale VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 573 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. BMI at delivery calculated from the most recent among those with severe–critical illness, 18 days (1– pregnancy weight before delivery. For patients with 47) among those with mild–moderate illness, and 1 BMI at delivery and without prenatal (or preconcep- day (0–2) for asymptomatic individuals. Of those who tional) BMI, imputed BMI values were the back- were asymptomatic with a positive SARS-CoV-2 test transformed predicted values based on the model. result, 97% were tested in the context of universal Analyses were performed with SAS 9.4. Adjust- screening at the time of delivery admission. ments were not made for multiple comparisons. The majority of critically ill patients were classi- fied as such owing to respiratory failure (Table 1). RESULTS Overall, the most common patient-reported symp- Of 1,291 pregnant patients with a positive SARS- toms were cough (34%), dyspnea (19%), and myalgias CoV-2 test result over the study time period, 1,219 (19%). Those classified as severe most frequently had (94%) had a singleton gestation and tested positive tachypnea or hypoxia. Although the majority of during pregnancy, and were included in the analysis patients with severe and critical illness had abnormal (Fig. 1). Of these, 579 (47%) were asymptomatic, 326 results on chest radiologic imaging (chest X-ray or (27%) had mild illness, 173 (14%) had moderate ill- computed tomography scan), only a small proportion ness, 98 (8%) had severe illness, and 43 (4%) had had more than 50% lung involvement (1% and 5%, respectively). critical illness (Fig. 1). Among the patients with Tests of trend were significant for differences in severe–critical illness, 11% were transported from another health care facility. age, median BMI, and insurance status across disease The median (interquartile range) gestational age severity (Table 2). The majority (53%) of enrolled at the time of first positive SARS-CoV-2 test result patients were of Hispanic ethnicity; however, there was 37.7 weeks of gestation (33.7–39.1). The majority was no trend in race–ethnicity distribution by sever- of SARS-CoV-2 tests were performed in the inpatient ity. Tests of trend were significant for differences in setting (67%). The number of days from the first pos- frequency of medical comorbidities including asthma itive SARS-CoV-2 test result to delivery varied by or chronic obstructive pulmonary disease, chronic disease severity, with a median of 4 days (1–28) hypertension, prepregnancy diabetes, chronic liver Fig. 1. Study cohort. First positive test result (molecular or antigen) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); coronavirus disease 2019 (COVID-19) classification based on data through delivery hospitalization. *Respiratory failure is use of any of the following: extracorporeal membrane oxygenation, continuous positive airway pressure, bi-level positive airway pressure, ventilation. Multiple organ dysfunction or failure is two or more of the following: cardiac arrest, impaired liver function, renal insufficiency (serum creatinine greater than 1.10 mg/dL), renal failure requiring dialysis, encephalopathy, any need for pressor support, thrombocytopenia (platelets less than 100,000). Other symptoms include fever, cough, sore throat, fatigue, muscle pain, chills, back pain, nausea, vomiting, joint pain, nasal stuffiness, conjunctivitis, confusion, loss of smell or taste, diarrhea, or other. MFMU, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units. Metz. COVID-19 Severity and Perinatal Outcomes. Obstet Gynecol 2021. 574 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 1. Coronavirus Disease 2019 (COVID-19) Disease Severity Classification for Study Cohort* Critical Severe Moderate Mild Asymptomatic Data Through Delivery Hospitalization (n543) (n598) (n5173) (n5326) (n5579) Respiratory failure 29 (67) Septic shock 8 (19) Multiple organ dysfunction or failure 26 (61) Death due to COVID-19 4 (9) Respiratory frequency greater than 30 breaths/min 29 (67) 70 (71) SpO less than 94% with O support 27 (63) 59 (60) 2 2 PaO or FiO less than 300 mm Hg 18 (42) 4 (4) 2 2 High-flow nasal cannula 1 (2) 6 (6) Lung infiltrates greater than 50% on CT or chest X-ray 2 (5) 1 (1) Abnormal chest imaging results (lung infiltrates less 31 (72) 51 (52) 47 (27.2) than or equal to 50%) Documentation of self-reported dyspnea 24 (56) 55 (56) 151 (87.3) Any other self-reported symptoms (excluding dyspnea) 35 (81) 84 (86) 171 (98.8) 326 (100) Cough 28 (65) 63 (64) 131 (75.7) 192 (58.9) Myalgia or body aches 15 (35) 40 (41) 76 (43.9) 101 (31.0) Fever 18 (42) 41 (42) 63 (36.4) 92 (28.2) Nasal stuffiness or rhinorrhea 3 (7) 24 (25) 65 (37.6) 111 (34.0) Headache 9 (21) 21 (21) 62 (35.8) 96 (29.4) Other symptoms 18 (42) 30 (31) 67 (38.7) 61 (18.7) Chills (shaking) 16 (37) 38 (39) 49 (28.3) 54 (16.6) Anosmia or loss of smell 8 (19) 12 (12) 43 (24.9) 78 (23.9) Fatigue 13 (30) 25 (26) 49 (28.3) 46 (14.1) Sore throat 9 (21) 20 (20) 39 (22.5) 63 (19.3) Nausea or vomiting 8 (19) 28 (29) 46 (26.6) 47 (14.4) Ageusia or loss of taste 6 (14) 12 (12) 42 (24.3) 67 (20.6) Back or joint pain 7 (16) 18 (18) 20 (11.6) 20 (6.1) Diarrhea 5 (12) 11 (11) 21 (12.1) 26 (8.0) Confusion 3 (7) 0 0 2 (0.6) Conjunctivitis 0 2 (2) 2 (1.2) 0 No symptoms 579 (100) COVID-19, coronavirus disease 2019; CT, computed tomography. Data are n (%). Many patients met multiple criteria for disease severity category. * First positive SARS-CoV-2 test result (nucleic acid or antigen) during pregnancy; COVID-19 classification based on available data through delivery hospitalization. Respiratory failure is use of any of the following: extracorporeal membrane oxygenation, continuous positive airway pressure, bi-level positive airway pressure, ventilation. Multiple organ dysfunction or failure is two or more of the following: cardiac arrest, impaired liver function, renal insufficiency (serum creatinine greater than 1.10 mg/dL), renal failure requiring dialysis, encephalopathy, any need for pressor support, thrombocytopenia (platelets less than 100,000). disease, and seizure disorder across disease severity. frequency of neonatal or fetal death by disease sever- Illness severity was not related to ABO blood type or ity is described in Table 3. presence of Rhesus factor (Table 2). A thromboembolic event occurred in eight Vital sign and laboratory findings by COVID-19 patients (6%, 95% CI 2–11%) in the severe–critical severity are described in Appendix 3, available online group; all of these events were deep venous throm- at http://links.lww.com/AOG/C219. Maternal and boses or pulmonary emboli. In comparison, there was perinatal deaths are presented in Table 3. Four mater- one (0.2%) thromboembolism in the mild–moderate nal deaths (0.3%) were thought to be due to COVID- group and none (0%) in the asymptomatic group 19; autopsies were not performed in all cases. Two (P,.001 for trend across severity) (Table 3). Of those other maternal deaths occurred during the study time with a venous thromboembolism, five received pro- period and were not related to infection; both had phylactic anticoagulation before the event, all in the severe COVID-19 before dying of other causes. The severe–critical group. VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 575 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 2. Baseline Demographic and Clinical Characteristics Disease Severity Critical–Severe Moderate–Mild Asymptomatic P for Characteristic (n5141) (n5499) (n5579) Trend* Age (y) 3066.2 2966.3 2866.3 .006 BMI (kg/m ) 32.3 (27.1–37.5) 29.0 (25.2–34.3) 28.3 (24.6–33.0) ,.001 30 or higher 66 (58.4) 202 (44.7) 198 (40.0) ,.001 40 or higher 20 (17.7) 40 (8.9) 35 (7.1) .002 Race–ethnicity .77 Non-Hispanic Black 30 (21.3) 122 (24.4) 123 (21.2) Non-Hispanic White 13 (9.2) 88 (17.6) 80 (13.8) Hispanic 81 (57.4) 246 (49.3) 324 (56.0) Other, unknown, or more than 1 race 17 (12.1) 43 (8.6) 52 (9.0) No prior pregnancy 20 wk or longer 48 (34.0) 153 (30.7) 187 (32.3) .98 Previous preterm birth (20 to less than 37 13 (9.2) 49 (9.8) 61 (10.6) .59 wk) Previous cesarean birth 33 (23.4) 112 (22.4) 122 (21.1) .49 Previous hypertensive disorder of 16 (11.3) 69 (13.8) 45 (7.8) .02 pregnancy Employed 61 (61.6) 219 (55.7) 194 (50.3) .03 Private insurance 46 (33.6) 160 (32.3) 124 (21.9) ,.001 Smoked during this pregnancy 5 (3.5) 18 (3.6) 27 (4.7) .39 Any substance use during this pregnancy 6 (4.3) 32 (6.4) 21 (3.6) .22 Blood type .16 A 45 (31.9) 161 (32.3) 154 (26.6) B 17 (12.1) 67 (13.5) 64 (11.1) AB 3 (2.1) 19 (3.8) 20 (3.5) O 76 (53.9) 251 (50.4) 340 (58.8) Rh-positive 133 (94.3) 466 (93.6) 541 (93.6) .81 Immunocompromising condition 3 (2.1) 11 (2.2) 4 (0.7) .06 Asthma or chronic obstructive pulmonary 29 (20.6) 85 (17.0) 51 (8.8) ,.001 disease Pregestational diabetes 14 (9.9) 18 (3.6) 17 (2.9) .002 Thrombophilia 0 4 (0.8) 3 (0.5) .79 Chronic hypertension 16 (11.3) 35 (7.0) 29 (5.0) .007 Chronic cardiovascular disease 2 (1.4) 9 (1.8) 3 (0.5) .11 Chronic renal disease 1 (0.7) 2 (0.4) 0 .08 Chronic liver disease 3 (2.1) 2 (0.4) 1 (0.2) .01 Thyroid disease 10 (7.1) 22 (4.4) 22 (3.8) .13 Neurocognitive disorder 2 (1.4) 23 (4.6) 10 (1.7) .25 Neuromuscular disorder 2 (1.4) 1 (0.2) 1 (0.2) .07 Seizure disorder 5 (3.5) 5 (1.0) 4 (0.7) .02 Inflammatory bowel disease 1 (0.7) 2 (0.4) 0 .08 BMI, body mass index. Data are mean6SD, median (interquartile range), or n (%) unless otherwise specified. Number of missing values: BMI (n5159), previous pregnancy (n51), employment status (n5341), insurance status (n520), blood type (n52), Rh factor (n52). * P-value based on Cochran-Armitage trend test for binary variables, score test from multinomial logistic regression for multinomial variables, or Jonckheere-Terpstra trend test for continuous variables. All patients identified as Hispanic ethnicity, regardless of race, were categorized as Hispanic. Other race includes non-Hispanic Asian, Native Hawaiian/Pacific Islander, American Indian/Alaskan Native, unknown, and more than one race. Overall, 6% of the cohort had an antepartum COVID-19. Among the patients initially classified as admission for treatment of COVID-19 separate from asymptomatic during the delivery hospitalization, one the delivery hospitalization. Fifty-nine (5%) were admit- had a hospital readmission with ICU care for COVID- ted to the ICU either during the pregnancy or within 42 19 after delivery discharge but before 42 days postpar- days postpartum (Table 3). The majority of the ICU tum. Other ICU admissions in asymptomatic patients admissions (45/59, 76%) were for an indication of were for indications unrelated to COVID-19. 576 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 3. Perinatal Outcomes by Coronavirus Disease 2019 (COVID-19) Severity Critical–Severe (n5141) Moderate–Mild (n5499) Asymptomatic RR aRR* RR aRR* (ref) P for Outcome (95% CI) (95% CI) (95% CI) (95% CI) (n5579) Trend Maternal death 6 (4.3) 0 0 ,.001 Venous thromboe- 8 (5.7) 1 (0.2) 0 ,.001 mbolism Maternal ICU 50 (35.5) 68.4 (21.7–216) 57.5 (17.8– 6 (1.2) 2.32 (0.58– 2.07 (0.51– 3 (0.5) ,.001 admission 186.3) 9.23) 8.34) Cesarean birth 84 (59.6) 1.75 (1.47–2.09) 1.57 (1.30–1.90) 169 (33.9) 1.00 (0.84– 0.94 (0.81– 197 (34.0) ,.001 1.18) 1.09) Postpartum 21 (14.9) 2.05 (1.26–3.35) 2.02 (1.18–3.45) 45 (9.0) 1.24 (0.83– 1.21 (0.78– 42 (7.3) .008 hemorrhage 1.86) 1.87) Hypertensive 57 (40.4) 2.15 (1.65–2.79) 1.61 (1.18–2.20) 119 (23.8) 1.27 (1.01– 1.24 (0.98– 109 (18.8) ,.001 disorders of 1.60) 1.58) pregnancy Fetal or neonatal 6 (4.3) 11 (2.2) 11 (1.9) .15 death Fetal loss at less36 4 than 20 wk Fetal loss at 2014 5 wk or later Neonatal death 2 1 2 Preterm birth (less 59 (41.8) 3.51 (2.61–4.72) 3.53 (2.42–5.14) 76 (15.2) 1.28 (0.94– 1.36 (0.97– 69 (11.9) ,.001 than 37 wk) 1.73) 1.91) Spontaneous 10 (16.9) 30 (39.5) 35 (50.7) Indicated 49 (83.1) 46 (60.5) 34 (49.3) Live birth 137 489 570 SGA (less than the 11 (8.0) 0.81 (0.44–1.51) 1.22 (0.63–2.37) 59 (12.2) 1.23 (0.87– 1.48 (1.02– 56 (9.9) .93 10th 1.74) 2.16) percentile) Birth weight (g) 2,8416726.1 2364 (2479 to 2385 (2510 to 3,1746600.1 232 (2106 261 (2138 3,2056603.9 ,.001 ¶ ¶ ¶ ¶ 2249) 2261) to 43) to 15) NICU admission 69 (50.4) 3.15 (2.45–4.06) 3.12 (2.32–4.20) 94 (19.2) 1.20 (0.93– 1.24 (0.93– 91 (16.0) ,.001 1.56) 1.66) ref, referent; RR, relative risk; aRR, adjusted relative risk; ICU, intensive care unit; SGA, small for gestational age; NICU, neonatal intensive care unit. Data are n (%) or mean6SD unless otherwise specified. Number of missing values: size for gestational age (n56). * All models adjusted for maternal age, body mass index, and major medical comorbidity; hypertensive disorders of pregnancy and preterm birth also adjusted for obstetric history of preterm birth or hypertensive disorder of pregnancy; cesarean birth also adjusted for history of cesarean birth. Cochran-Armitage trend test for binary variables or Jonckheere-Terpstra trend test for continuous variables. Venous thromboembolism defined as cerebral venous sinus thrombosis, arterial thrombosis cerebrovascular accident, pulmonary embolism, deep venous thrombosis. Postpartum hemorrhage defined as estimated blood loss greater than 1,000 mL. Hypertensive disorders of pregnancy defined as hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; eclampsia; preeclampsia with or without severe features; gestational hypertension; and chronic hypertension with superimposed preeclampsia according to American College of Obstetricians and Gynecologists definitions. Difference in means. Neonatal intermediate or intensive care unit. Rates for cesarean birth, postpartum hemorrhage, (aRR 3.53, 95% CI 2.42–5.14) compared with asymp- hypertensive disorders of pregnancy and preterm tomatic patients. In a sensitivity analysis in which BMI birth were 36.9%, 8.9%, 23.4% and 16.7%, respec- was imputed for those with missing values (n5159, tively. Adverse maternal and neonatal outcomes were 13%), the adjusted association between severe– more frequent in patients with severe COVID-19 critical and postpartum hemorrhage was no longer illness (Table 3). In adjusted analyses, severe–critical significant (aRR 1.68, 95% CI 1.00–2.84). COVID-19 was associated with a higher risk of cesar- Preterm births among patients with severe– ean birth (adjusted relative risk [aRR] 1.57, 95% CI critical illness were indicated (rather than spontane- 1.30–1.90), postpartum hemorrhage (aRR 2.02, 95% ous) in 83% of cases compared with 61% in patients CI 1.18–3.45), hypertensive disorders of pregnancy with mild–moderate illness and 49% in patients who (aRR 1.61, 95% CI 1.18–2.20), and preterm birth were symptomatic (P,.001 for trend across severity VOL. 137, NO. 4, APRIL 2021 Metz et al COVID-19 Severity and Perinatal Outcomes 577 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. for indicated delivery among preterm births). Of those associated with higher risk of NICU admission and induced preterm (n567), COVID-19 was the primary lower birth weight compared with neonates of asymp- indication for induction of labor in 3%. The most tomatic patients. common indications for induction among the preterm Our findings regarding preterm birth and NICU births were hypertensive disorders of pregnancy admission are consistent with a previous report. (33%), stillbirth (16%), and preterm prelabor rupture However, in our cohort, the increased risk of preterm of membranes (13%). Of those who underwent pre- birth was driven by indicated, rather than spontane- term cesarean birth (n5106), COVID-19 was the pri- ous, preterm birth. Our work also expands what is mary indication for cesarean in 22%. The other known about perinatal outcomes in patients with common indications for cesarean among those with COVID-19 by demonstrating that severe or critical preterm births were nonreassuring fetal status (29%), illness is associated with a number of other adverse hypertensive disorders of pregnancy (15%), and perinatal outcomes for both the patient and the abnormal presentation (11%). neonate. Severe–critical maternal illness was associated We observed a 6% VTE rate in the severe–critical with NICU admission and lower birth weight. Mild– group. National Institutes of Health treatment guide- moderate maternal illness was marginally associated lines recommend prophylactic anticoagulation in with small-for-gestational-age birth weight, although pregnant hospitalized patients with COVID-19. this association was no longer significant when BMI Nonetheless, our data are consistent with those in was imputed for those with missing values. Among nonpregnant patients in that critically ill patients with patients who were induced or had cesarean birth, COVID-19 have a high rate of VTE even when COVID-19 was the indication for induction or cesar- receiving prophylactic anticoagulation. Ongoing ean in 32 of 112 (29%) of the patients with severe– randomized controlled trials are evaluating whether critical illness, 12 of 330 (4%) with mild–moderate therapeutic anticoagulation reduces risk of VTE when illness, and 16 of 352 (5%) who were asymptomatic. compared with prophylactic anticoagulation. Further In total, 1.0% (95% CI 0.5–1.8%) of neonates study is also needed to determine the need for anti- tested positive for SARS-CoV-2 before discharge. coagulation in the setting of less severe COVID-19 The rate of positive neonatal SARS-CoV-2 test results illness during pregnancy as there was an isolated among live births was 1.5% in the severe–critical venous thromboembolic event in the mild–moderate group, 0.6% in the mild–moderate group, and 1.2% group (1 in 499). in the asymptomatic group. The percentage of neo- The rate of a positive neonatal SARS-CoV-2 test nates with a 5-minute Apgar score of 3 or less was result was approximately 1% across sites. The major- 2.9% in the severe–critical, 0.2% in the mild– ity of these neonates were breastfed or breast and moderate, and 0.7% in the asymptomatic group. The bottle fed. We were limited in our capacity to evaluate majority (900/1,190 with available data, 76%) of for vertical transmission because only clinical testing neonates in the cohort were breastfed or breast and was available, and, in many cases, this does not bottle fed. Among patients in whom an offer of include serial testing of the neonate and evaluation maternal–neonatal separation owing to SARS-CoV-2 of the placenta as required to confirm vertical trans- infection was documented (n5448, 37%), 312 were mission rather than horizontal transmission after actually separated (26% of total population): 59 of birth. Nonetheless, despite a majority of neonates 64 (92%) with severe–critical illness, 77 of 126 (61%) receiving at least some breastfeeding, positive viral with mild–moderate illness, and 176 of 258 (68%) who testing in the neonates was infrequent. were in the asymptomatic group. Initial Morbidity and Mortality Weekly Report data demonstrated an increased risk for hospitalization DISCUSSION among pregnant patients compared with females of We found that 12% of pregnant patients with reproductive age who were not pregnant; however, COVID-19 had severe or critical illness. Patients with it was not possible to delineate whether the patient severe or critical COVID-19 are at risk for a number was simply admitted for delivery (rather than of perinatal complications including cesarean birth, COVID-19 complications). Our data indicate that, hypertensive disorders of pregnancy, and preterm overall, 6% of pregnant patients who tested positive birth. Those with severe or critical illness also had for SARS-CoV-2 had a hospital admission for increased frequency of venous thromboembolism COVID-19 separate from their delivery hospitaliza- compared with those with less severe illness. In tion. Although this is similar to the 5.8% hospitaliza- addition, severe or critical maternal illness was tion rate published by the Centers for Disease Control 578 Metz et al COVID-19 Severity and Perinatal Outcomes OBSTETRICS & GYNECOLOGY © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. and Prevention for nonpregnant reproductive-age be interpreted in the context of overlapping signs (eg females, direct comparisons cannot be made given hypertension and lab abnormalities) and symptoms differences in sampling strategy. In addition, patients (eg headache) between preeclampsia with severe with critical illness may have required delivery to features and severe or critical COVID-19; however, improve maternal status during what was initially a standard American College of Obstetricians and COVID-19 hospitalization. Gynecologists’ diagnostic criteria were used for this Centers for Disease Control and Prevention data endpoint to minimize subjectivity. In addition, owing demonstrate an increased risk of death from COVID- to the clinical importance and descriptive nature of 19 and ICU admission among pregnant patients com- the data, analyses were not adjusted for multiple com- pared with nonpregnant patients. Recent hospital- parisons; therefore, some findings could be attributed level administrative data also demonstrate increased to chance. Finally, treatment for COVID-19 was rap- risks of both of these outcomes among patients with idly evolving during the study period, and the effect of COVID-19 compared with those without COVID-19. current treatments on outcomes could not be Our maternal death rate was 0.3% (3/1,000 patients evaluated. with COVID-19), and the ICU admission rate was Strengths of this study include the standardized 4.8% (48/1,000). Both of these rates are higher than collection methods of detailed medical record abstrac- those previously published. A small proportion of the tion by trained and certified perinatal research staff. increase may reflect transports requiring critical care The study included 33 demographically and socio- from other facilities to MFMU tertiary care centers. economically diverse sites, which makes these data However, transports only comprised 11% of the more generalizable than single-center data. In addi- severe–critical study population. Therefore, the high- tion, the size of the study population afforded by er rates may also reflect increased ascertainment of multiple sites allowed for a larger sample to evaluate these outcomes through manual medical record differences in outcomes by disease severity. We abstraction rather than relying on administrative data. included patients with positive test results in both Consistent with prior studies, risk factors for the inpatient and outpatient setting, which expands severe or critical COVID-19 included older age, knowledge related to COVID-19 in pregnancy, as the increased BMI, and underlying medical comorbidities results are not biased by only including inpatients. such as asthma, chronic hypertension, and pregesta- These results suggest that pregnant patients with tional diabetes. The majority of pregnant patients with higher levels of COVID-19 severity are at higher risk COVID-19 in our cohort were of Hispanic ethnicity of perinatal complications. Clinicians should be aware (53%); however, there was no trend in COVID-19 of these risks and consider strategies to mitigate severity based on race–ethnicity. 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