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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 theEunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network* OBJECTIVE:To describe coronavirus disease 2019 (COVID-19) severity in pregnant patients and evaluate the association between disease severity and perinatal outcomes. METHODS:We conducted an observational cohort study of all pregnant patients with a singleton gestation and a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who delivered at 1 of 33 U.S. hospitals in 14 states from March 1 to July 31, 2020. Disease severity was classified by National Insti- tutes of Health criteria. Maternal, fetal, and neonatal outcomes were abstracted by centrally trained andcertified perinatal research staff. We evaluated trends in maternal characteristics and outcomes across COVID- 19 severity classes and associations between severity and outcomes by multivariable modeling. RESULTS:A total of 1,219 patients were included: 47% asymptomatic, 27% mild, 14% moderate, 8% severe, 4% critical. Overall, 53% were Hispanic; there was no trend in race–ethnicity distribution by disease severity. Those with more severe illness had older mean age, higher median body mass index, and pre-existing medical co- morbidities. Four maternal deaths (0.3%) were attributed to COVID-19. Frequency of perinatal death or a positive *A list of other members of the NICHD MFMU Network is available in the Appendix 1 online at http://links.lww.com/AOG/C219. From the Departments of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah, University of Texas Medical Branch at Galveston, Galveston, Texas, Northwestern University, Chicago, Illinois, Uni- versity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, Columbia University, New York, New York, University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Houston, Texas, University of Pennsylvania, Philadelphia, Pennsylvania, Brown University, Providence, Rhode Island, University of Alabama at Birmingham, Birmingham, Alabama, MetroHealth Medical Center, Case Western Reserve University, Cleve- land, Ohio, The Ohio State University, Columbus, Ohio, University of Pittsburgh, Pittsburgh, Pennsylvania, and University of Texas at Austin, Austin, Texas; the George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy ShriverNational Institute of Child Health and Human Development, Bethesda, Maryland. This work is funded by theEunice Kennedy ShriverNational Institute of Child Health and Human Development (UG1 HD087230, UG1 HD027869, UG1 HD027915, UG1 HD034208, UG1 HD040500, UG1 HD040485, UG1 HD053097, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD040512, UG1 HD087192, U10 HD036801) and the National Cen- ter for Advancing Translational Sciences (UL1TR001873). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Presented at the Society for Maternal-Fetal Medicine’s 41st Annual Pregnancy Meeting, held virtually, January 25–30, 2021. Dr. Rouse, Editor-in-Chief, and Dr. Metz, Associate Editor, Obstetrics, for Obstetrics & Gynecology, were not involved in the review or decision to publish this article. Each author has confirmed compliance with the journal’s requirements for authorship. Published online ahead-of-print February 8, 2021. Corresponding author: Torri D. Metz, MD, MS, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT; email: [email protected] Financial Disclosure: Torri Metz is the site Principal Investigator (PI) for a Pfizer RSV vaccination study, a Novavax RSV vaccination study, and a Gestvision study of the validity of a point-of- care preeclampsia test. She also receives royalties for two UpToDate topics on vaginal birth after cesarean. Brenna Hughes disclosed receiving funds from Merck. Cynthia Gyamfi-Bannerman disclosed that moneywas paid to her institution from NICHD/ NHLBI and AMAG/SMFM. She has received funds from Sera Prognostics as a Medical Advisory Board Member. Alan Tita reports money was paid to his institution from Pfizer. The other authors did not report any potential conflicts of interest. © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/21 © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. VOL. 137, NO. 4, APRIL 2021OBSTETRICS & GYNECOLOGY571 neonatal SARS-CoV-2 test result did not differ by sever- ity. Adverse perinatal outcomes were more frequent among patients with more severe illness, including 6% (95% CI 2–11%) incidence of venous thromboembolism among those with severe–critical illness compared with 0.2% in mild–moderate and 0% in asymptomatic (P,.001 for trend across severity). In adjusted analyses, severe– critical COVID-19 was associated with increased risk of cesarean birth (59.6% vs 34.0%, adjusted relative risk [aRR] 1.57, 95% CI 1.30–1.90), hypertensive disorders of pregnancy (40.4% vs 18.8%, aRR 1.61, 95% CI 1.18–2.20), and preterm birth (41.8% vs 11.9%, aRR 3.53, 95% CI 2.42–5.14) compared with asymptomatic patients. Mild– moderate COVID-19 was not associated with adverse perinatal outcomes compared with asymptomatic patients. CONCLUSION:Compared with pregnant patients with SARS-CoV-2 infection without symptoms, those with severe–critical COVID-19, but not those with mild– moderate COVID-19, were at increased risk of perinatal complications. (Obstet Gynecol 2021;137:571–80) DOI: 10.1097/AOG.0000000000004339 E xisting reports of coronavirus disease 2019 (COVD-19) in pregnant patients are largely lim- ited to single centers or geographic areas, registries requiring self-referral or health care practitioner refer- ral, and meta-analyses of case series in the inpatient setting. 1–4 A systematic review and meta-analysis of cohort studies with pregnant patients found an associ- ation between COVID-19 and both preterm birth and neonatal intensive care unit (NICU) admission. 5 However, available data did not permit examination of other important perinatal outcomes, and the meta- analysis includes some studies in which COVID-19 was diagnosed based on clinical suspicion without testing. In addition, data from the United States are largely derived from those contained in theMorbidity and Mortality Weekly Report, 6which are administrative data provided by public health departments without details regarding clinical disease course. Recently Adhikari et al 7performed a retrospective cohort study of pregnant patients delivering at a single academic center and found no association between COVID-19 and a composite adverse perinatal out- come of preterm birth, preeclampsia with severe fea- tures, or cesarean birth. However, 95% of the cohort had asymptomatic or mild disease, and it remains unknown whether perinatal outcomes differ by COVID-19 severity. The relationship between COVID-19 and perinatal outcomes among pregnant patients in the United States remains largely unknown.TheEunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network consists of 12 centers with more than 30 separate aca- demic and community hospitals. Together these sites represent the demographic, racial-ethnic and socio- economic diversity present in the United States. At each site, trained research staff have the capacity to identify all pregnant patients with a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivering there and to perform detailed medical record abstraction using a standard- ized protocol. Therefore, we aimed to describe COVID-19 disease severity in a large, diverse cohort of pregnant patients. In addition, we aimed to com- pare perinatal outcomes among patients based on dis- ease severity. We hypothesized that patients with more severe COVID-19 would have worse perinatal outcomes. METHODS This study was an observational cohort of all pregnant patients with a positive SARS-CoV-2 molecular or antigen test result who delivered at 1 of 33 NICHD MFMU sites (six community and 27 academic) in 14 states between March 1, 2020, and July 31, 2020. Patients were included if they had a positive test result at any point during pregnancy (inpatient or outpa- tient), and a singleton gestation. Both symptomatic patients and asymptomatic patients were included. During the study time period, some of the sites performed SARS-CoV-2 testing for all patients admit- ted for delivery regardless of symptoms or known exposures. Patients with positive antibody testing alone were not included. Owing to public health concern and potential selection bias, data were collected under a waiver of informed consent with institutional review board approval at each of the participating institutions. Data were analyzed by an independent data coordinating center. Gestational age at the time of the positive SARS- CoV-2 test result was calculated based on best obstetric estimated date of delivery and the date of the first positive SARS-CoV-2 test result. Detailed electronic medical record abstraction was performed by local perinatal research teams at each MFMU site after centralized training and certification by the data coordinating center. Data quality checks were per- formed on an ongoing basis to ensure high-quality data across all participating sites. Descriptive data regarding maternal COVID-19 disease severity were abstracted from the electronic medical record, including symptoms, vital signs, © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 572Metz et alCOVID-19 Severity and Perinatal OutcomesOBSTETRICS & GYNECOLOGY imaging results, laboratory values, treatments, com- plications, and high-intensity interventions including intubation, dialysis, and extracorporeal membrane oxygenation. Hospitalizations and intensive care unit (ICU) admissions during pregnancy through 42 days postpartum also were enumerated. Self-reported symptoms were recorded based on record review from the patient encounter at the time of a SARS- CoV-2 test that included a duration of onset on or 14 days before the test or diagnosis date. Patients were classified as having asymptomatic, mild, moderate, severe, or critical illness based on National Institutes of Health guidelines for severity of clinical presentation (see Appendix 2, available online at http://links.lww.com/AOG/C219). 8Classification was based on self-reported symptoms as described above or the patient’s worst clinical status from their presentation for SARS-CoV-2 testing through deliv- ery discharge. Maternal outcomes included death, ICU admis- sion, venous thromboembolism, postpartum hemor- rhage, hypertensive disorders of pregnancy, and cesarean birth. Venous thromboembolism was defined as cerebral venous sinus thrombosis, arterial thrombosis cerebrovascular accident, pulmonary em- bolism, or deep venous thrombosis. Postpartum hemorrhage was defined as estimated blood loss greater than 1,000 mL. 9Hypertensive disorders of pregnancy were defined according to American Col- lege of Obstetricians and Gynecologists criteria for hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; eclampsia; preeclampsia with or without severe features; gestational hyperten- sion; and chronic hypertension with superimposed preeclampsia. 10 Medical records were reviewed for outpatient visits and re-admissions through 42 days postpartum for maternal outcomes. Neonatal outcomes included perinatal death, positive molecular or antigen SARS-CoV-2 test result during birth admission, and preterm birth before 37 weeks of gestation. Among live births, additional outcomes included neonatal intermediate care unit or NICU admission, birth weight, 5-minute Apgar score 3 or less as a marker of adverse neonatal outcomes, 11 and small-for-gestational-age birth weight less than the 10th percentile based on the Duryea et al 12 nomogram. Neonates were followed only through the delivery hospitalization. Summary statistics were calculated for baseline characteristics. Race and ethnicity data were abstracted from the medical record and were based on patient self-report at the time of clinical care. All patients identified as Hispanic ethnicity, regardless ofrace, were categorized as Hispanic. The“other race” category includes non-Hispanic Asian, Native Hawai- ian or Pacific Islander, American Indian/Alaskan Native, unknown or more than one race. These cate- gories were collapsed to make comparisons between groups with low frequency of patients in the other race categories. In addition, those with severe and critical illness were grouped together for statistical compari- sons, as were those with mild and moderate illness. The Cochran-Armitage trend test for binary variables, score test from multinomial logistic regression for multinomial variables, or Jonckheere-Terpstra trend test for continuous variables were used to assess trends in baseline characteristics and perinatal outcomes across the severe–critical, mild–moderate, and asymptomatic categories. Severe–critical COVID-19 and mild–moderate COVID-19 were each compared with asymptomatic patients using multivariable modeling. Multivariable modeling was not performed for outcomes with low frequencies including maternal death, stillbirth or neo- natal death, maternal venous thromboembolism, or positive SARS-CoV-2 test results for the neonate. Co- variates for modeling were selected based on clinical relevance and included maternal age, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) at first prenatal visit or (if that was not available) preconceptionally, and major medical comorbidity (any of the following: asthma of any severity or chronic obstructive pulmonary dis- ease, chronic hypertension, or pregestational diabetes). Models for hypertensive disorders of pregnancy and preterm birth also included a covariate for obstetric history (categorized as no prior pregnancy 20 weeks of gestation or longer, history of preterm birth or hypertensive disorder of pregnancy, or prior pregnancy without preterm birth or hypertensive disorder of pregnancy). The model for cesarean birth included history of cesarean birth (categorized as no prior pregnancy 20 weeks of gestation or longer, history of only vaginal births, or any prior cesarean birth) in addition to the baseline demographic vari- ables above. For continuous outcomes, generalized linear models were used to estimate the difference of means and 95% CIs. For categorical outcomes, modified Poisson regression models were used to estimate relative risks and 95% CIs. A sensitivity analysis was performed in which missing BMI values were imputed based on a generalized linear model and adjusted models were re-run. The imputation modeled the natural-log scale BMI with linear, quadratic, and cubic natural-log scale © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. VOL. 137, NO. 4, APRIL 2021Metz et alCOVID-19 Severity and Perinatal Outcomes573 BMI at delivery calculated from the most recent pregnancy weight before delivery. For patients with BMI at delivery and without prenatal (or preconcep- tional) BMI, imputed BMI values were the back- transformed predicted values based on the model. Analyses were performed with SAS 9.4. Adjust- ments were not made for multiple comparisons. RESULTS Of 1,291 pregnant patients with a positive SARS- CoV-2 test result over the study time period, 1,219 (94%) had a singleton gestation and tested positive during pregnancy, and were included in the analysis (Fig. 1). Of these, 579 (47%) were asymptomatic, 326 (27%) had mild illness, 173 (14%) had moderate ill- ness, 98 (8%) had severe illness, and 43 (4%) had critical illness (Fig. 1). Among the patients with severe–critical illness, 11% were transported from another health care facility. The median (interquartile range) gestational age at the time of first positive SARS-CoV-2 test result was 37.7 weeks of gestation (33.7–39.1). The majority of SARS-CoV-2 tests were performed in the inpatient setting (67%). The number of days from the first pos- itive SARS-CoV-2 test result to delivery varied by disease severity, with a median of 4 days (1–28)among those with severe–critical illness, 18 days (1– 47) among those with mild–moderate illness, and 1 day (0–2) for asymptomatic individuals. Of those who were asymptomatic with a positive SARS-CoV-2 test result, 97% were tested in the context of universal screening at the time of delivery admission. The majority of critically ill patients were classi- fied as such owing to respiratory failure (Table 1). Overall, the most common patient-reported symp- toms were cough (34%), dyspnea (19%), and myalgias (19%). Those classified as severe most frequently had tachypnea or hypoxia. Although the majority of patients with severe and critical illness had abnormal results on chest radiologic imaging (chest X-ray or computed tomography scan), only a small proportion had more than 50% lung involvement (1% and 5%, respectively). Tests of trend were significant for differences in age, median BMI, and insurance status across disease severity (Table 2). The majority (53%) of enrolled patients were of Hispanic ethnicity; however, there was no trend in race–ethnicity distribution by sever- ity. Tests of trend were significant for differences in frequency of medical comorbidities including asthma or chronic obstructive pulmonary disease, chronic 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 ShriverNational Institute of Child Health and Human Development Maternal-Fetal Medicine Units. Metz. COVID-19 Severity and Perinatal Outcomes. Obstet Gynecol 2021. © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 574Metz et alCOVID-19 Severity and Perinatal OutcomesOBSTETRICS & GYNECOLOGY disease, and seizure disorder across disease severity. Illness severity was not related to ABO blood type or presence of Rhesus factor (Table 2). Vital sign and laboratory findings by COVID-19 severity are described in Appendix 3, available online at http://links.lww.com/AOG/C219. Maternal and perinatal deaths are presented in Table 3. Four mater- nal deaths (0.3%) were thought to be due to COVID- 19; autopsies were not performed in all cases. Two other maternal deaths occurred during the study time period and were not related to infection; both had severe COVID-19 before dying of other causes. Thefrequency of neonatal or fetal death by disease sever- ity is described in Table 3. A thromboembolic event occurred in eight patients (6%, 95% CI 2–11%) in the severe–critical group; all of these events were deep venous throm- boses or pulmonary emboli. In comparison, there was one (0.2%) thromboembolism in the mild–moderate group and none (0%) in the asymptomatic group (P,.001 for trend across severity) (Table 3). Of those with a venous thromboembolism, five received pro- phylactic anticoagulation before the event, all in the severe–critical group. Table 1.Coronavirus Disease 2019 (COVID-19) Disease Severity Classification for Study Cohort* Data Through Delivery HospitalizationCritical (n543)Severe (n598)Moderate (n5173)Mild (n5326)Asymptomatic (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 2less than 94% with O 2support 27 (63) 59 (60) Pa O 2or FiO 2less than 300 mm Hg 18 (42) 4 (4) 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 than or equal to 50%)31 (72) 51 (52) 47 (27.2) 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 symptoms579 (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). © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. VOL. 137, NO. 4, APRIL 2021Metz et alCOVID-19 Severity and Perinatal Outcomes575 Overall, 6% of the cohort had an antepartum admission for treatment of COVID-19 separate from the delivery hospitalization. Fifty-nine (5%) were admit- ted to the ICU either during the pregnancy or within 42 days postpartum (Table 3). The majority of the ICU admissions (45/59, 76%) were for an indication ofCOVID-19. Among the patients initially classified as asymptomatic during the delivery hospitalization, one had a hospital readmission with ICU care for COVID- 19 after delivery discharge but before 42 days postpar- tum. Other ICU admissions in asymptomatic patients were for indications unrelated to COVID-19. Table 2.Baseline Demographic and Clinical Characteristics CharacteristicDisease Severity Pfor Trend* Critical–Severe (n5141)Moderate–Mild (n5499)Asymptomatic (n5579) Age (y) 3066.2 2966.3 2866.3 .006 BMI (kg/m 2) 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 wk)13 (9.2) 49 (9.8) 61 (10.6) .59 Previous cesarean birth 33 (23.4) 112 (22.4) 122 (21.1) .49 Previous hypertensive disorder of pregnancy16 (11.3) 69 (13.8) 45 (7.8) .02 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 disease29 (20.6) 85 (17.0) 51 (8.8),.001 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. © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 576Metz et alCOVID-19 Severity and Perinatal OutcomesOBSTETRICS & GYNECOLOGY Rates for cesarean birth, postpartum hemorrhage, hypertensive disorders of pregnancy and preterm birth were 36.9%, 8.9%, 23.4% and 16.7%, respec- tively. Adverse maternal and neonatal outcomes were more frequent in patients with severe COVID-19 illness (Table 3). In adjusted analyses, severe–critical COVID-19 was associated with a higher risk of cesar- ean birth (adjusted relative risk [aRR] 1.57, 95% CI 1.30–1.90), postpartum hemorrhage (aRR 2.02, 95% CI 1.18–3.45), hypertensive disorders of pregnancy (aRR 1.61, 95% CI 1.18–2.20), and preterm birth(aRR 3.53, 95% CI 2.42–5.14) compared with asymp- tomatic patients. In a sensitivity analysis in which BMI was imputed for those with missing values (n5159, 13%), the adjusted association between severe– critical and postpartum hemorrhage was no longer significant (aRR 1.68, 95% CI 1.00–2.84). Preterm births among patients with severe– critical illness were indicated (rather than spontane- ous) in 83% of cases compared with 61% in patients with mild–moderate illness and 49% in patients who were symptomatic (P,.001 for trend across severity Table 3.Perinatal Outcomes by Coronavirus Disease 2019 (COVID-19) Severity OutcomeCritical–Severe (n5141) Moderate–Mild (n5499) Asymptomatic (ref) (n5579)Pfor Trend † RR (95% CI)aRR* (95% CI)RR (95% CI)aRR* (95% CI) Maternal death 6 (4.3) 0 0,.001 Venous thromboe- mbolism ‡ 8 (5.7) 1 (0.2) 0,.001 Maternal ICU admission50 (35.5) 68.4 (21.7–216) 57.5 (17.8– 186.3)6 (1.2) 2.32 (0.58– 9.23)2.07 (0.51– 8.34)3 (0.5),.001 Cesarean birth 84 (59.6) 1.75 (1.47–2.09) 1.57 (1.30–1.90) 169 (33.9) 1.00 (0.84– 1.18)0.94 (0.81– 1.09)197 (34.0),.001 Postpartum hemorrhage § 21 (14.9) 2.05 (1.26–3.35) 2.02 (1.18–3.45) 45 (9.0) 1.24 (0.83– 1.86)1.21 (0.78– 1.87)42 (7.3) .008 Hypertensive disorders of pregnancy ║ 57 (40.4) 2.15 (1.65–2.79) 1.61 (1.18–2.20) 119 (23.8) 1.27 (1.01– 1.60)1.24 (0.98– 1.58)109 (18.8),.001 Fetal or neonatal death6 (4.3) 11 (2.2) 11 (1.9) .15 Fetal loss at less than 20 wk364 Fetal loss at 20 wk or later145 Neonatal death 2 1 2 Preterm birth (less than 37 wk)59 (41.8) 3.51 (2.61–4.72) 3.53 (2.42–5.14) 76 (15.2) 1.28 (0.94– 1.73)1.36 (0.97– 1.91)69 (11.9),.001 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 10th percentile)11 (8.0) 0.81 (0.44–1.51) 1.22 (0.63–2.37) 59 (12.2) 1.23 (0.87– 1.74)1.48 (1.02– 2.16)56 (9.9) .93 Birth weight (g) 2,8416726.12364 (2479 to 2249) ¶ 2385 (2510 to 2261) ¶ 3,1746600.1232 (2106 to 43) ¶ 261 (2138 to 15) ¶ 3,2056603.9,.001 NICU admission # 69 (50.4) 3.15 (2.45–4.06) 3.12 (2.32–4.20) 94 (19.2) 1.20 (0.93– 1.56)1.24 (0.93– 1.66)91 (16.0),.001 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. © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. VOL. 137, NO. 4, APRIL 2021Metz et alCOVID-19 Severity and Perinatal Outcomes577 for indicated delivery among preterm births). Of those induced preterm (n567), COVID-19 was the primary indication for induction of labor in 3%. The most common indications for induction among the preterm births were hypertensive disorders of pregnancy (33%), stillbirth (16%), and preterm prelabor rupture of membranes (13%). Of those who underwent pre- term cesarean birth (n5106), COVID-19 was the pri- mary indication for cesarean in 22%. The other common indications for cesarean among those with preterm births were nonreassuring fetal status (29%), hypertensive disorders of pregnancy (15%), and abnormal presentation (11%). Severe–critical maternal illness was associated with NICU admission and lower birth weight. Mild– moderate maternal illness was marginally associated with small-for-gestational-age birth weight, although this association was no longer significant when BMI was imputed for those with missing values. Among patients who were induced or had cesarean birth, COVID-19 was the indication for induction or cesar- ean in 32 of 112 (29%) of the patients with severe– critical illness, 12 of 330 (4%) with mild–moderate illness, and 16 of 352 (5%) who were asymptomatic. In total, 1.0% (95% CI 0.5–1.8%) of neonates tested positive for SARS-CoV-2 before discharge. The rate of positive neonatal SARS-CoV-2 test results among live births was 1.5% in the severe–critical group, 0.6% in the mild–moderate group, and 1.2% in the asymptomatic group. The percentage of neo- nates with a 5-minute Apgar score of 3 or less was 2.9% in the severe–critical, 0.2% in the mild– moderate, and 0.7% in the asymptomatic group. The majority (900/1,190 with available data, 76%) of neonates in the cohort were breastfed or breast and bottle fed. Among patients in whom an offer of maternal–neonatal separation owing to SARS-CoV-2 infection was documented (n5448, 37%), 312 were actually separated (26% of total population): 59 of 64 (92%) with severe–critical illness, 77 of 126 (61%) with mild–moderate illness, and 176 of 258 (68%) who were in the asymptomatic group. DISCUSSION We found that 12% of pregnant patients with COVID-19 had severe or critical illness. Patients with severe or critical COVID-19 are at risk for a number of perinatal complications including cesarean birth, hypertensive disorders of pregnancy, and preterm birth. Those with severe or critical illness also had increased frequency of venous thromboembolism compared with those with less severe illness. In addition, severe or critical maternal illness wasassociated with higher risk of NICU admission and lower birth weight compared with neonates of asymp- tomatic patients. Our findings regarding preterm birth and NICU admission are consistent with a previous report. 5 However, in our cohort, the increased risk of preterm birth was driven by indicated, rather than spontane- ous, preterm birth. Our work also expands what is known about perinatal outcomes in patients with COVID-19 by demonstrating that severe or critical illness is associated with a number of other adverse perinatal outcomes for both the patient and the neonate. We observed a 6% VTE rate in the severe–critical group. National Institutes of Health treatment guide- lines recommend prophylactic anticoagulation in pregnant hospitalized patients with COVID-19. 8 Nonetheless, our data are consistent with those in nonpregnant patients in that critically ill patients with COVID-19 have a high rate of VTE even when receiving prophylactic anticoagulation. 13 Ongoing randomized controlled trials are evaluating whether therapeutic anticoagulation reduces risk of VTE when compared with prophylactic anticoagulation. Further study is also needed to determine the need for anti- coagulation in the setting of less severe COVID-19 illness during pregnancy as there was an isolated venous thromboembolic event in the mild–moderate group (1 in 499). The rate of a positive neonatal SARS-CoV-2 test result was approximately 1% across sites. The major- ity of these neonates were breastfed or breast and bottle fed. We were limited in our capacity to evaluate for vertical transmission because only clinical testing was available, and, in many cases, this does not include serial testing of the neonate and evaluation of the placenta as required to confirm vertical trans- mission rather than horizontal transmission after birth. 14 Nonetheless, despite a majority of neonates receiving at least some breastfeeding, positive viral testing in the neonates was infrequent. InitialMorbidity and Mortality Weekly Reportdata demonstrated an increased risk for hospitalization among pregnant patients compared with females of reproductive age who were not pregnant; however, it was not possible to delineate whether the patient was simply admitted for delivery (rather than COVID-19 complications). 15 Our data indicate that, overall, 6% of pregnant patients who tested positive for SARS-CoV-2 had a hospital admission for COVID-19 separate from their delivery hospitaliza- tion. Although this is similar to the 5.8% hospitaliza- tion rate published by the Centers for Disease Control © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 578Metz et alCOVID-19 Severity and Perinatal OutcomesOBSTETRICS & GYNECOLOGY and Prevention for nonpregnant reproductive-age females, direct comparisons cannot be made given differences in sampling strategy. In addition, patients with critical illness may have required delivery to improve maternal status during what was initially a COVID-19 hospitalization. Centers for Disease Control and Prevention data 6 demonstrate an increased risk of death from COVID- 19 and ICU admission among pregnant patients com- pared with nonpregnant patients. Recent hospital- level administrative data 16 also demonstrate increased risks of both of these outcomes among patients with COVID-19 compared with those without COVID-19. Our maternal death rate was 0.3% (3/1,000 patients with COVID-19), and the ICU admission rate was 4.8% (48/1,000). Both of these rates are higher than those previously published. A small proportion of the increase may reflect transports requiring critical care from other facilities to MFMU tertiary care centers. However, transports only comprised 11% of the severe–critical study population. Therefore, the high- er rates may also reflect increased ascertainment of these outcomes through manual medical record abstraction rather than relying on administrative data. Consistent with prior studies, 5risk factors for severe or critical COVID-19 included older age, increased BMI, and underlying medical comorbidities such as asthma, chronic hypertension, and pregesta- tional diabetes. The majority of pregnant patients with COVID-19 in our cohort were of Hispanic ethnicity (53%); however, there was no trend in COVID-19 severity based on race–ethnicity. We found a higher frequency of current employment and private insur- ance among those with higher disease severity, which may in part reflect transport of patients with higher illness severity to tertiary care centers included in the MFMU. Limitations of this analysis include the fact that not all sites were performing universal screening for SARS-CoV-2 infection during the entire study period. Overall, the mean gestational age at infection was late in the third trimester, which was at least partially attributable to the inclusion criterion for this analysis being delivery by July 31, 2020; COVID-19 was not widely prevalent in the United States until March 2020. Therefore, the association between COVID-19 and early pregnancy complications such as miscar- riage or congenital anomalies could not be evaluated. Many of the NICHD MFMU sites are in urban locations which may limit generalizability to more rural settings; however, both academic and community-based hospitals were included. Results regarding hypertensive disorders of pregnancy mustbe interpreted in the context of overlapping signs (eg hypertension and lab abnormalities) and symptoms (eg headache) between preeclampsia with severe features and severe or critical COVID-19; however, standard American College of Obstetricians and Gynecologists’diagnostic criteria were used for this endpoint to minimize subjectivity. In addition, owing to the clinical importance and descriptive nature of the data, analyses were not adjusted for multiple com- parisons; therefore, some findings could be attributed to chance. Finally, treatment for COVID-19 was rap- idly evolving during the study period, and the effect of current treatments on outcomes could not be evaluated. Strengths of this study include the standardized collection methods of detailed medical record abstrac- tion by trained and certified perinatal research staff. The study included 33 demographically and socio- economically diverse sites, which makes these data more generalizable than single-center data. In addi- tion, the size of the study population afforded by multiple sites allowed for a larger sample to evaluate differences in outcomes by disease severity. We included patients with positive test results in both the inpatient and outpatient setting, which expands knowledge related to COVID-19 in pregnancy, as the results are not biased by only including inpatients. These results suggest that pregnant patients with higher levels of COVID-19 severity are at higher risk of perinatal complications. Clinicians should be aware of these risks and consider strategies to mitigate complications when possible. REFERENCES 1. Khoury R, Bernstein PS, Debolt C, Stone J, Sutton DM, Simp- son LL, et al. 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MMWR Morb Mortal Wkly Rep 2020;69:769–75. doi: 10.15585/mmwr.mm6925a1 16. Jering KS, Claggett BL, Cunningham JW, Rosenthal N, Var- deny O, Greene MF, et al. Clinical characteristics and outcomes of hospitalized women giving birth with and without COVID- 19. JAMA Int Med;2021 Jan 15 [Epub ahead of print]. doi: 10. 1001/jamainternmed.2020.9241 PEER REVIEW HISTORY Received January 15, 2021. Received in revised form January 28, 2021. Accepted January 29, 2021. Peer reviews and author corre- spondence are available at http://links.lww.com/AOG/C220. © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 580Metz et alCOVID-19 Severity and Perinatal OutcomesOBSTETRICS & GYNECOLOGY

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