key: cord-0870568-m98g03jp
authors: BRANDT, Justin S.; HILL, Jennifer; REDDY, Ajay; SCHUSTER, Meike; PATRICK, Haylea S.; ROSEN, Todd; SAUER, Mark V.; BOYLE, Carla; ANANTH, Cande V.
title: Epidemiology of COVID-19 in Pregnancy: Risk Factors and Associations with Adverse Maternal and Neonatal Outcomes
date: 2020-09-25
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.09.043
sha: fcafd16daa2ac20431f4bbef9023ea2764ce1bd5
doc_id: 870568
cord_uid: m98g03jp

Background COVID-19 may be associated with adverse maternal and neonatal outcomes in pregnancy, but there is little controlled data to quantify the magnitude of these risks or to characterize the epidemiology and risk factors. Objective To quantify the associations of COVID-19 with adverse maternal and neonatal outcomes in pregnancy and to characterize the epidemiology and risk factors. Methods We performed a matched case-control study of pregnant patients with confirmed COVID-19 (cases) who delivered between 16 and 41 weeks’ gestation from March 11-June 11, 2020. Uninfected pregnant women (controls) were matched to COVID-19 cases on a 2:1 ratio based on delivery date. Maternal demographic characteristics, COVID-19 symptoms, laboratory evaluations, obstetrical and neonatal outcomes, and clinical management were chart abstracted. The primary outcomes included (i) a composite of adverse maternal outcome, defined as preeclampsia, venous thromboembolism, antepartum admission, maternal intensive care unit admission, need for mechanical ventilation, supplemental oxygen, or maternal death; and (ii) a composite of adverse neonatal outcome, defined as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, five-minute Apgar score <5, persistent category 2 fetal heart rate tracing despite intrauterine resuscitation, or neonatal death. In order to quantify the associations between exposure to mild and severe/critical COVID-19 and adverse maternal and neonatal outcomes, unadjusted and adjusted analyses were performed using conditional logistic regression (to account for matching), with matched-pair odds ratio (OR) and 95% confidence interval (CI) based on 1000 bias-corrected bootstrap resampling as the effect measure. Associations were adjusted for potential confounders. Results 61 confirmed COVID-19 cases were enrolled during the study period (mild disease: n=54, 88.5%; severe disease: n=6, 9.8%; and critical disease: n=1, 1.6%). The odds of adverse composite maternal outcome were 3.4 times higher among cases compared to controls (18.0% versus 8.2%, adjusted OR 3.4, 95% CI 1.2-13.4). The odds of adverse composite neonatal outcome were 1.7 times higher in the case group compared to the control group (18.0% versus 13.9%, adjusted OR 1.7, 95% CI 0.8-4.8). Stratified analyses by disease severity indicated that the morbidity associated with COVID-19 in pregnancy was largely driven by the severe/critical disease phenotype. Major risk factors for associated morbidity were Black and Hispanic race, advanced maternal age, medical comorbidities, and antepartum admissions related to COVID-19. Conclusions COVID-19 during pregnancy is associated with increased risk for adverse maternal and neonatal outcomes, an association that is primarily driven by morbidity associated with severe/critical COVID-19. Black and Hispanic race, obesity, advanced maternal age, medical comorbidities, and antepartum admissions related to COVID-19 are risk factors for associated morbidity.

Patients were considered to be cases if they had positive COVID-19 testing and delivered 156 between 16.0 and 41.6 weeks' gestation. Cases were categorized as mild, severe, or critical 157 disease according to previously published criteria (9). Mild disease was defined as 158 nonpneumonia and mild pneumonia; severe disease was defined as dyspnea, respiratory 159 frequency ≥30/min, blood oxygen saturation ≤93%, partial pressure of arterial oxygen to 160 fraction of inspired oxygen ratio <300, and lung infiltrates >50% on chest x-ray; and critical 161 disease was defined as respiratory failure, septic shock, and multiple organ failure. Patients 162 were eligible to be cases if initial COVID-19 testing was negative, but subsequent testing during 163 the delivery hospitalization became positive. Patients were excluded if they were persons under 164 investigation (PUI) without confirmatory testing or had negative COVID-19 testing or if they 165 were hospitalized but discharged prior to delivery. 166 167 Each COVID-19 case was matched to two controls by delivery date. Prior to April 10, controls 168 were selected as the first two patients who delivered between 16.0 and 41.6 weeks' gestation 169

April 10, controls were selected if they had negative COVID-19 testing and delivered on the 171 same date as the cases. On days with two or more cases, we identified the next two eligible 172 controls as potential matches. During the three-month study period, there were 61 pregnant patients diagnosed with COVID-233 matched to two controls by delivery date. Eleven (18%) cases were enrolled in the first month, 235 28 (45.9%) were enrolled in the second, and 22 (36.1%) were enrolled in the third. Among the 236 cases, disease severity was mild (n=54, 88.5%), severe (n=6, 9.8%), and critical (n=1, 1.6%). 237

Demographic characteristics for cases and controls are described in Table 1 Overall 61.1% of patients with mild COVID-19 were asymptomatic. Of the 11 patients who were 247 enrolled during the first month of the study period, 1 (9.1%) patient was asymptomatic; testing 248 of the asymptomatic patient was due to a high-risk exposure. During the latter two months of 249 the study period, 32 (64%) patients were asymptomatic. The most common symptoms for mild 250 disease were cough, fever, and myalgias ( Table 2 ). In contrast, all patients with severe/critical 251 disease reported symptoms, with cough, shortness of breath, and fever being the most 252 common symptoms. All patients with severe/critical disease required supplemental oxygen, 253 and some also received other interventions such as hydroxychloroquine (n=4, 57.1%) in the 254 early part of the study period and corticosteroids (n=4, 57.1%) in the latter part. In contrast, 255 J o u r n a l P r e -p r o o f only one patient with mild disease received treatment; the patient was treated with antibiotics 256 for a bacterial pneumonia. 257 258 Laboratory results are described in Table 3 . Patients with mild disease had similar mean white 259 blood cell and platelet counts and median lymphocyte counts and transaminases. In contrast, 260 cases with severe/critical COVID-19 had higher risks of white blood cell count <9.5 cells/L, 261 platelets <150,000/mm 3 , lymphocytes <10 9 cells/L, and elevated alanine aminotransferase >45 262 units/L or aspartate transaminase >35 units/L, compared to controls. 263

Obstetrical and neonatal outcomes are described in Table 4 . Cases with mild disease had similar 265 obstetrical outcomes compared to controls. However, cases with severe/critical disease had 266 more adverse obstetrical outcomes, including earlier gestational age of delivery (34.0 versus 267 38.7 weeks; mean difference 4.8 weeks, 95% CI 2.6, 6.9). Cases were more likely to deliver 268 preterm <37, <34, and <28 weeks' gestation, compared to controls. Patients with severe/critical 269 COVID-19 also had higher risks of antepartum admissions, cesarean delivery, chorioamnionitis, 270 preeclampsia, and persistent category 2 fetal heart rate tracing despite intrauterine 271 resuscitation, and required longer hospital stays, compared to controls. Table 5 . Comparing all COVID-19 cases to controls, the unadjusted odds ratios of 293 adverse maternal and neonatal outcome were 2.7 (95% CI 1.0-10.0) and 1.4 (95% CI 0.6-3.6) 294 respectively. After adjusting for advanced maternal age, obesity, race, and comorbid medical 295 problems, the adjusted odds of adverse maternal and neonatal outcomes were 3.4 (95% CI 1.2-296 13.4) and 1.7 (95% CI 0.8-4.8), respectively. In analyses stratified by disease severity, the odds 297 of adverse maternal and neonatal outcome were similar for mild COVID-19 cases versus 298 J o u r n a l P r e -p r o o f controls ( 

The main finding of this study is that severe/critical disease drive morbidity associated with 313 COVID-19 in pregnancy. As broader testing for COVID-19 becomes available, the prevalence of 314 asymptomatic and mild disease has increased. The results of this study can provide some 315 reassurance for most pregnant patients. 316 317 After implementation of universal testing, we found that 64% of cases were asymptomatic. Our 318 rate of asymptomatic disease was lower than other reports of asymptomatic presentation on 319 labor and delivery. For example, in the initial experience of Columbia with universal testing, 320 Although the study was robust and included maternal and neonatal outcomes that were 368 rigorously abstracted, the data was abstracted from delivery hospitalizations. We recognize 369 that some patients with COVID-19 in the community may not have required hospitalization or 370 were hospitalized, but remained undelivered over the course of this project. These patients 371

were not included in this study. As such, the current analysis may bias towards more severe 372 phenotype for patients with severe/critical COVID-19 during the first three months of the 373 pandemic. 374

The study's sample size was relative small, leading to imprecision in the effect measure 376 estimates. We included two matched controls per COVID-19 case (which may have resulted in 377 improved power), but the small sample size limited conclusions about rare outcomes. For 378 example, a large retrospective cohort study that included 3309 births found higher rates of 379 intrauterine fetal demise during the pandemic compared to a pre-pandemic period (22), but we 380 were underpowered for rare outcomes such as this. There is great need for robust research on 381 this topic, which is why have presented this data at this time, but we intend to continue data 382 collection for the purposes of larger studies in the future. The CDC recommends that pregnant patients take steps to minimize acquisition of the infection 390 that causes COVID-19 due to potential for severe disease compared to non-pregnant patients 391 (5). Most pregnant patients with COVID-19 have mild disease, and this is not associated with 392 substantial risk of adverse maternal and neonatal outcomes. However, the results of this 393 matched case-control study show the driver for risk in pregnancy is severe/critical disease. 394

Moreover, specific risk factors are associated with the severe/critical disease phenotype, 395

including Black and Hispanic race, advanced maternal age, obesity, medical comorbidities, and 396 antepartum admission related to COVID-19. While the results of this study support the CDC's 397 conclusion, the main findings suggest disease severity and specific risk factors drive risk 398 associated with COVID-19 during pregnancy. 399 J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Data presented as n (percent). † Data presented as mean (standard deviation). ‡ Data presented as median (interquartile range). WBC, white blood count; AST, aspartate aminotransferase; ALT, alanine aminotransferase. 474 Table 4 

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Birth weight (grams) † 3230 (549) 2293 (1104) 3246 (605) Apgar, 1-minute ‡ 9 (9-9) 9 (1-9) 9 (9-9) -Apgar, 5-minute ‡ 9 (9-9) 9 (5-9) 9 (9-9) - Composite maternal outcome includes venous thromboembolism, preeclampsia, intensive care unit admission, mechanical ventilation, antepartum admission, supplemental oxygen, and death. Composite neonatal outcome includes respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, fiveminute Apgar score <5, persistent category 2 fetal heart rate tracing, and neonatal death ORs were adjusted for advanced maternal age, obesity, race, and comorbid medical problem; 95% CIs were based on 1000 biascorrected bootstrap resampling method. Note: The analyses for severe/critical cases vs controls were not estimable due to small numbers and the lack of convergence of the conditional logistic regression model. 482