key: cord-0732290-2s2ypnij
authors: OAKES, Megan C.; KERNBERG, Annessa S.; CARTER, Ebony B.; FOELLER, Megan E.; PALANISAMY, Arvind; RAGHURAMAN, Nandini; KELLY, Jeannie C.
title: Pregnancy as a risk factor for severe coronavirus 2019 (COVID-19) disease using standardized clinical criteria
date: 2021-01-22
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2021.100319
sha: aed7779561e98c2c798073e04e9127afb49917f7
doc_id: 732290
cord_uid: 2s2ypnij

BACKGROUND: As of November 18, 2020, over 11 million people have been infected with coronavirus disease 2019 (COVID-19) and almost 250,000 people have died from the disease in the US, less than one year since its discovery. Although literature is beginning to emerge on pregnancy as a risk factor for severe COVID-19, these studies are heterogeneous and use primary outcomes such as intensive care unit admission or hospitalization as surrogate markers that may subject analyses to misclassification bias in pregnant patients. OBJECTIVE: We aim determine the risk of severe COVID-19 among pregnant women with symptomatic COVID-19 compared to non-pregnant women using non-admission based, standardized clinical criteria for severe disease. STUDY DESIGN: This is a retrospective cohort study of women aged 13-45 years and diagnosed with symptomatic COVID-19 between May 28-July 22, 2020. The primary outcome was severe COVID-19 as defined by two sets of non-admission based, clinical criteria: the World Health Organization Ordinal Scale for Clinical Improvement and the Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. Adjusted risk ratios were estimated using multivariable logistic regression analyses. RESULTS: Of 262 women aged 13-45 years with symptomatic COVID-19, 22 (8.4%) were pregnant and 240 (91.6%) were non-pregnant. After adjusting for covariates potentially associated with the primary outcome, symptomatic pregnant women were at significantly increased risk for severe COVID-19 compared to non-pregnant women using both the World Health Organization Ordinal Scale for Clinical Improvement (aRR 3.59, 95% CI 1.49-7.01) and Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (aRR 5.65, 95% CI 1.36-17.31) criteria. CONCLUSION: Pregnancy significantly increases the risk for severe COVID-19 as defined by non-admission based, clinical criteria.

As of November 18, 2020, over 11 million people have been infected with coronavirus disease 2019 (COVID- 19) and 247,834 have died from the disease in the US, less than one year since its discovery. 1 Of the many clinical characteristics that make combatting COVID-19 challenging is the varied and sometimes rapid progression of COVID-19 infection, representing a spectrum ranging from persistently asymptomatic infection to acute respiratory failure. Among pregnant women admitted for delivery, asymptomatic infection appears to be the most common presentation of COVID-19; however, up to one-third may progress to symptomatic disease, including critical illness, during a single admission. 2 With limited therapeutic options and no vaccine yet widely available to the general population, the focus of pandemic control has been on primary prevention and identifying those at greatest risk for severe disease. In June 2020, the Centers for Disease Control and Prevention (CDC) included pregnancy as a risk factor for severe COVID-19 based on hospitalization rates; although their data was limited, as pregnancy status was not available for 71% of patients and admission indication was not specified. 3 Recent literature continues to support pregnancy as a risk factor for severe 5 However, the diagnosis of severe COVID-19 in these studies is heterogeneous, using primary outcomes such as intensive care unit admission or hospitalization as surrogate markers that are subject to misclassification bias in pregnant patients.

While there is no gold standard, twodefinitions of severe COVID-19 have been published previously. Shortly after the identification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the classification of COVID-19 as a Class B notifiable disease in China, the Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (NCPERET) set specific clinical criteria defining severe disease as a way to better describe the emerging viral illness. 6 Notably, the NCPERET criteria is the same recommended by the Society of Maternal-Fetal Medicine (SMFM) to define severe disease with the exception that dyspnea is excluded. 7 More recently, the World Health Organization (WHO) proposed an ordinal scale of clinical endpoints to facilitate interpretation and combination of results across studies and trials (https://www.who.int/teams/blueprint/covid -19) . Contemporary clinical studies regarding COVID-19 have widely adopted ordinal scales similar to the WHO Ordinal Scale for Clinical Improvement (WHOOSCI) to define severe disease in non-pregnant individuals. [8] [9] [10] [11] To better describe the relationship between pregnancy and severe COVID-19, we tested the hypothesis that pregnancy is associated with a higher risk of severe disease in symptomatic COVID-19 positive patients using two sets of standardized clinical criteria recommended by the NCPERET and WHO, rather than inpatient or intensive care unit admission, to define severe disease.

This is a retrospective cohort study of all women aged 13-45 years who had a positive SARS-CoV-2 test by polymerase chain reaction (PCR) or rapid antigen testing and were symptomatic with COVID-19 between May 28-July 22, 2020 at a single, urban tertiary hospital. The Washington University School of Medicine Human Research Protection Office granted exemption as part of a quality improvement initiative. Patients with asymptomatic COVID-19, such as those found to have a positive test result as a part of universal testing prior to delivery or surgery, were excluded.

The primary outcome was severe COVID-19 defined in two ways: NCPERET criteria, 6 and the WHOOSCI (https://www.who.int/teams/blueprint/covid-19). Severe COVID-19 using the NCPERET criteria is defined as: dyspnea, respiratory rate of > 30 breaths per minute, blood oxygen saturation of < 93%, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) of <300, or lung infiltrates involving >50% on imaging (Table 1) . Disease severity using the WHOOSCI is determined by oxygen and organ support requirements. Scores of 5-7 are classified as severe disease (Table 1) .

All patients with a positive SARS-CoV-2 test during the study period were identified, then the cohort narrowed by sex and age. A detailed chart review of clinical notes, medical history, pregnancy status, vital signs, laboratory studies, and imaging pertaining to the index encounter following a positive test was performed by trained staff. Patients were deemed to have severe disease based upon the presence of any criteria for severe disease by either the NCPERET or WHOOSCI during the index encounter. Patients meeting criteria for severe disease were only counted once for each set of criteria, regardless of the number of criteria present for severe disease.

The primary outcome of severe disease was compared between pregnant and non-pregnant women.The presence of medical co-morbidities deemed by the Centers for Disease Control and Prevention (CDC) as risk factors for severe disease (with the exception of pregnancy) was determined by chart review. Co-morbidities were assessed individually, summed to generate a composite co-morbidity risk score, and compared between pregnant and non-pregnant women. 12 Baseline patient characteristics were compared using χ 2 or Fisher's exact for categorical variables and Student's t-test or Wilcoxon rank-sum for continuous variables, as appropriate.

Normality of distribution for continuous variables was tested using the Kolmogorov-Smirnov test. Relative risk (RR) and 95% confidence intervals (95% CI) were calculated for the primary outcome using each set of clinical criteria separately. Multivariable logistic regression was used to adjust for confounders, identified as variables which had at least a 10% effect size on the RR. The Zhang method was used to approximate an adjusted relative risk from the adjusted odds ratio given the frequency of our primary outcome. 13 The final model was tested with the Hosmer-Lemeshow goodness-of-fit test. No a priori sample size estimation was performed, as all patients who met inclusion criteria during the study period were included. Statistical analyses were performed using STATA software, version 16.1 (StataCorp LLC, College Station, TX).

A total of 301 patients who met inclusion criteria tested positive for SARS-CoV-2 within the study period. Of those, 39 were asymptomatic (n=26, 66.6% pregnant; n=13, 33. Among symptomatic women, 7 (31.8%) pregnant and 17 (7.1%) non-pregnant patients were classified as having severe COVID-19 using the NCPERET criteria. Using the WHOOSCI criteria, 3 (13.6%) pregnant and 6 (2.50%) non-pregnant patients were classified as having severe COVID-19. Composite co-morbidity, ethnicity, and insurance type were selected as covariates for the multivariable logistic regression model given clinical and statistical significance; however, only when ethnicity and insurance remained in the final model did the Hosmer-Lemeshow goodness-of-fit test reach a P>0.05, meaning no significant difference between observed and expected values within the final model. After adjusting for these covariates, pregnant patients were significantly more likely to have severe disease compared to non-pregnant patients using both the NCPERET criteria and the WHOOSCI (aRR 3.59, 95% CI 1.49-7.01 and aRR 5.65, 95% CI 1.36-17.31, respectively) ( Table 3) . While there was no significant difference in the length of stay between pregnant and non-pregnant patients, more pregnant patients with severe COVID-19 were admitted to an intensive care unit (7 (100%) vs 9 (50%), P=0.03, and 3 (100%) vs 5 (83.3%), P=1.00), by NCPERET and WHOOSCI criteria, respectively). There were no deaths in either group.

Among women presenting with symptomatic COVID-19, pregnancy was associated with a significantly higher risk of severe disease by standardized NCPERET and WHOOSCI criteria compared to non-pregnant counterparts.

Our results mirror the described clinical course of pregnant women infected with both COVID-19 and other respiratory viral illnesses (namely, influenza). 2, 5, [14] [15] [16] [17] During the 2009 influenza pandemic (H1N1), pregnant women accounted for 5% of all deaths yet only represented 1% of the population, a marked disproportion in distribution of severe disease. 15 In a systematic review of H1N1, pregnancy was demonstrated to be a risk factor for hospitalization, intensive care unit admission, and death when compared to non-pregnant women of similar age. 16 While many pregnant women with H1N1 had severe disease, pregnant women with additional co-morbidities identified by the Advisory Committee on Immunization Practices (ACIP) as risk factors for severe disease were more likely to develop severe disease than those without additional risk factors. This is in contrast to findings from a recently published multi-center case control study, in which pregnant women were found to have a greater risk for severe COVID-19 independent of select co-morbidities. 17 Our finding of pregnancy as a risk factor for severe COVID-19 is similar to several recently published studies. 5, 17 In multi-center matched case-control study, Badr et al found that, compared to non-pregnant controls, pregnant women were significantly more likely to require oxygen supplementation (36.04% vs 17.24%, P=0.006) and endotracheal intubation (10.16% vs 1.67%, P=0.022). 5 Although these select end-points differ from our study, we note a similar proportion of pregnant and non-pregnant women requiring ventilation with organ support in our study, which is classified as WHOOSCI score 7 (9.1% and 1.3%, respectively). In a multi-center case-control study, Debolt et al found that pregnant women were more likely to experience the composite primary outcome of death, need for intubation, extracorporeal membrane oxygenation (ECMO), non-invasive positive pressure ventilation or supplemental oxygen via high flow nasal cannula compared to non-pregnant women (aOR 4.6, 95% CI 1.2-18.2). 17 Importantly, the authors highlight that while non-pregnant controls had a higher prevalence of select comorbidities, pregnancy still emerged as a risk factor for the composite primary outcome.

Similarly, in our study, non-pregnant women had a higher composite co-morbidity risk score than pregnant women (1.0 + 1.1 vs 0.6 + 0.7, P=0.06). Although this was not included in the final multivariable logistic regression model, we conclude that pregnancy is a risk factor for severe COVID-19 in symptomatic women that is likely independent of other co-morbidities.

Our results add to the growing body of literature describing pregnancy as a risk factor for severe disease; however, there are important distinctions to consider. The primary outcome of severe COVID-19 was defined by two sets of clinical criteria in our study. Although similar findings are noted, using admission to an intensive care unit as the primary outcome for severe disease may have subjected results from previously published studies to misclassification bias given inability to account for obligatory hospitalization during pregnancy for delivery, and differential hospital protocols for admitting pregnant patients with COVID-19 to an intensive care unit. 5, 18 We see this reflected in our own data, with a greater proportion of pregnant patients with severe COVID-19 defined by either the NCPERET or WHOOSCI criteria being admitted to an intensive care unit compared to non-pregnant patients without a significant difference in length of stay.

Additionally, a majority of pregnant women positive for COVID-19 during our study period were asymptomatic compared to non-pregnant patients (54.2% vs 5.1%, respectively). This is consistent with findings prior observational studies of pregnant patients with COVID-19, likely attributed to the widespread universal testing policies on obstetric units. [19] [20] [21] [22] [23] We specifically included only women symptomatic with COVID-19 in our study in order to minimize the risk of sampling bias, which may have affected prior studies. 5

One of the major challenges in management of the COVID-19 pandemic is the wide spectrum in severity of disease and urgent need to better predict risk factors for progression. 2 Biologic plausibility of our finding of pregnancy as an independent risk factor for severe COVID-19 can be drawn from known immunologic and physiologic modulations in pregnancy. The number of CD3+ T lymphocytes (CHD4+ and CD8+), as well as Th1 and Th2 responses to mitogentic or antigenic lymphocyte stimulation, decrease during pregnancy. 24, 25 Following infection and replication within cells infected with SARS-CoV-2, pyroptosis (inflammation-mediated programmed cell death in response to a pathogenic stimulus) occurs, releasing damageassociated molecular proteins and stimulating a pro-inflammatory response. 26 T cells are attracted to the site of infection; however, as the response is modulated in the context of pregnancy, altered clearance of infected cells may favor severe disease.

Further, the immunomodulatory properties of progesterone may also be implicated in the increased risk for severe disease in pregnancy. Progesterone has been shown to suppress the maternal immune response and alter the balance between Th1 and Th2 responses. 27 This shift to Th2-dominant, cell-mediated immunity is thought to be implicated in increased severity of respiratory viral illnesses. In one mouse model of influenza A infection, treatment with progesterone resulted in a decrease of both virus-specific antibody levels and circulating CD8+ T cells. 28 When challenged with influenza A following progesterone treatment, increased severe disease was noted. Additionally, physiologic changes of the maternal respiratory system complicate the response to infection. Increases in minute ventilation, oxygen consumption, and chest wall compliance; reduction in expiratory reserve volume, functional residual capacity, and residual volume; and upward displacement of the maternal diaphragm all result in a decreased ability to compensate for respiratory disease. 29, 30 Together, these decreases in adaptive immunity and physiologic changes of pregnancy help to explain the observed increase risk for severe COVID-19. As the rising number of cases continues to put a strain on the demands of healthcare providers, refining the prediction of which patients are at high risk for the development of severe disease is ever important. Pregnant women who develop symptoms from COVID-19 should be closely monitored given the risk for severe disease.

Larger, prospective studies are needed to continue to understand the implications of severe COVID-19 in pregnancy on both maternal and neonatal outcomes. Currently, clinical criteria for defining severe COVID-19 are neither universal, nor specific to pregnancy. A two-fold difference in the absolute number of patients classified as having severe disease between the NCPERET and WHOOSCI (7 vs 3 and 17 vs 6, respectively) in both the pregnant and nonpregnant groups underscores the importance of developing universally standardized definitions inclusive of pregnant women to determine the true prevalence of severe COVID-19 and to better interpret and combine results of future studies. Notably, certain NCPERET parameters were unavailable for almost half of the patients otherwise defined as having severe disease by some other criteria. The WHOOSCI was specifically introduced as criteria that do not require extensive laboratory data or radiologic information for assessment of disease severity.

Pragmatically, using such an ordinal scale will likely lead to better uniform clinical classification, and thus could be more widely utilized across many populations

Our study used clinical criteria, not admission data, to determine severe COVID-19. We included symptomatic women with COVID-19 women who were followed both in the inpatient and outpatient setting, improving the generalizability of our findings. We assessed for the presence of all co-morbidities considered to be risk factors for severe disease by the CDC in evaluating the characteristics of our cohort. Most women were followed for >14 days, which decreased the likelihood of misclassification bias.

This study has potential limitations that should be considered. While generation of results from a single, tertiary care center decreased the variability in the management of women with severe COVID-19 in our study, this may limit the broad application of our findings. Given the retrospective nature of the study design, all cases meeting inclusion criteria were included in the analyses. Although we detected a difference in the primary outcome using both sets of clinical criteria between pregnant and non-pregnant women, larger studies are needed to validate our findings.

Both the NCPERET and WHOOSCI have been applied to diverse populations in the literature; however, these clinical criteria are not without their limitations. [7] [8] [9] [10] [11] Lower scores on the WHOOSCI involve subjective assessment (for example, score 2=limitation of activity); however, we limited our assessment to women with scores of > 5, which do not include assessment of activity limitation or hospitalization without requiring oxygen. The NCPERET criteria partially relies on laboratory data and radiologic assessment in qualifying severe disease, which not every patient underwent. Notably, 4/22 (18.1%) of pregnant were missing Pa/FiO 2 information, versus only 8/240 (3.3%) of non-pregnant women. The missing data, due to lack of arterial blood gas results, demonstrates a limitation of using the NCPERET criteria broadly to define severe disease. Using available data, there was a significant difference with more pregnant women having a Pa/FiO 2 <300 (11.1% vs 3.4%, P=0.04), suggesting that pregnant women are more likely to have severe COVID-19 by NCPERET criteria. Further, the application of both sets of criteria to the same population allowed for a detailed investigation of the relationship between pregnancy and severe COVID-19. Larger studies are needed to analyze the two sets of criteria for convergent validity.

In conclusion, pregnancy is an independent risk factor for severe COVID-19 in symptomatic, 

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