Abstract

Introduction

The novel coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global public health emergency with 21,294,845 infected people and 761,779 related deaths worldwide at the time of this writing.1 In the United States alone, 5,258,565 cases have been reported with 167,201 related deaths.1 Based on the early reports in pregnant women, the clinical course of COVID-19 is typically mild (86%), severe (9%), or critical (5%),2 which is similar to the clinical course distribution seen in the nonpregnant population, which is mild (81%), severe (14%), or critical (5%).3

SARS-CoV-2 infections seem to cause serious pulmonary manifestations, including pneumonia, which is the most prevalent nonobstetrical infection that occurs in pregnancy,4 acute respiratory distress syndrome, pervasive microemboli, and coagulation perturbations,5 and therefore an increase in morbidity and mortality among pregnant women is a reasonable concern. As with other infectious diseases, the normal maternal physiological changes that accompany pregnancy, including hypercoagulability, altered cell-mediated immunity,6 and the changes in pulmonary function, which cause a reduced total lung capacity at term and an inability to clear pulmonary secretions effectively,7 have been hypothesized to effect both the susceptibility to and clinical severity of pneumonia in pregnant women. The changes to the immune and respiratory systems that occur during pregnancy can increase their vulnerability to severe infection and hypoxic compromise. Common symptoms in pregnancy, such as physiological dyspnea, may delay a diagnosis when the pathologic dyspnea secondary to COVID-19 is not distinguished.8

There is a paucity of information regarding the outcomes of COVID-19 in pregnant women compared with nonpregnant women. A report from the Centers for Disease Control and Prevention (CDC) found that hospitalization was substantially higher among SARS-CoV-2–infected pregnant women when compared with nonpregnant women. Pregnant women were more frequently admitted to the intensive care unit (ICU) (1.5% vs 0.9%) and 0.5% of pregnant women required mechanical ventilation when compared with 0.3% of nonpregnant women. A total of 16 deaths (0.2%) were reported among pregnant women and 208 (0.2%) among nonpregnant women.9 However, in this report, data to distinguish between hospitalizations for COVID-19–related illness and admission for pregnancy-related conditions were not available. Knowledge of the course of the disease in pregnant vs nonpregnant women is essential to better understand the risk to our pregnant population. This study aimed to compare the clinical outcomes of severe and critical cases of COVID-19 in pregnant vs nonpregnant control women of reproductive age. We hypothesized that the clinical course and outcomes are worse in pregnant women, as has been demonstrated with other respiratory pathogens.10, 11, 12

Materials and Methods

This was a multicenter, case-control study of women with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infections who met the admission criteria for severe and critical COVID-19. We explored the clinical course and outcomes of pregnant women admitted with severe and critical COVID-19 status compared with nonpregnant control women of reproductive age. The data were collected from patients admitted to 4 hospitals in New York City and 1 in Philadelphia between March 12, 2020, and May 5, 2020. Our primary outcome variable was a composite morbidity that included death, a need for intubation, extracorporeal membrane oxygenation (ECMO), noninvasive positive pressure ventilation, including bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP), and a need for high-flow nasal cannula supplementation. Other treatment interventions, including medications used and the use of prone positioning, were also collected. Secondary outcomes included ICU admission, length of stay, frequency of discharge to home with O₂ supplementation, and frequency of discharge to a long-term care facility. During admission, delivery was performed for the usual obstetrical indications, however, beyond this, decisions about delivery was up to the individual providers’ discretion.

The inclusion criteria were defined as pregnant and nonpregnant women between 18 and 50 years of age who met the admission criteria for a diagnosis of severe or critical COVID-19 as defined by the World Health Organization and the Chinese Center for Disease Control and Prevention. Severe COVID-19 was defined as the presence of dyspnea (patient reported), a respiratory rate of ≥30 breaths per minute, blood O₂ saturation of ≤ 93% on room air, a partial pressure of arterial O₂ to the fraction of inspired oxygen of <300, and findings consistent with pneumonia on a chest x-ray.13, 14, 15 Critical COVID-19 was defined as respiratory failure requiring intubation or mechanical ventilation, septic shock, and multiple organ dysfunction or failure.13–15 Respiratory failure was defined as a need for invasive mechanical ventilation. Septic shock was defined as a need for vasopressors to maintain a mean arterial pressure (MAP) of ≥65 and serum lactate levels of >2 mmol/L despite a sufficient volume resuscitation along with ≥2 sepsis-related organ failure assessment criteria which include the following: a decline in the partial pressure of O₂ or fraction of inspired O₂, decline in platelet counts, rising bilirubin levels, decline in MAP, decline in the Glasgow Coma Scale, and a rise in serum creatinine.16 Multiple organ dysfunction or failure was defined as the presence of at least 2 of the following: renal impairment or failure (defined as a 3-fold increase in the baseline creatinine or need for dialysis17), liver failure (defined as an international normalized ratio of >1.5), a diagnosis of refractory hypoglycemia by the treating institution, or hepatic encephalopathy.18 A test result was considered positive for SARS-CoV-2 infection if the quantitative reverse transcription PCR (qRT-PCR) analysis of the specimen acquired from the respiratory tract in the form of a nasopharyngeal swab was positive for the presence of SARS-CoV-2. This method of confirming SARS-CoV-2 infection, in addition to the criteria used to define severe COVID-19 and critical COVID-19 cases, were uniform across all institutions. We excluded patients with comorbidities that are associated with an immunocompromised state including the following: an active malignancy, a history of transplant, a history of developmental delay, cerebral palsy, and trisomy 21 or other known aneuploidies. Regardless of a clinical suspicion, women with inconclusive or negative SARS-CoV-2 laboratory results were excluded. The variables of the obstetrical comorbidity index that is validated for use during labor and delivery to predict the risk of severe maternal morbidity were also collected.19 Severe maternal morbidity was classified according to the guidelines of the American College of Obstetricians and Gynecologists, the Society for Maternal Fetal Medicine, and the CDC.20 According to the CDC National Center for Health Statistics, preterm birth rate was defined as a singleton livebirth at <37 weeks’ gestation and early preterm birth as a singleton livebirth at <34 weeks of gestation.

The institutional review board at each institution approved this study. Data use agreements were obtained for collaboration among the sites. Data from each medical center’s electronic medical record (EMR) were abstracted by means of a Research Electronic Data Capture form. De-identified data were then merged into 1 data set managed by the primary author at Mount Sinai Hospital. We obtained data on the demographics, socioeconomic factors, presenting signs and symptoms, and the results of the laboratory and radiology tests that were performed. When applicable, the delivery data, including the maternal complications and neonatal outcomes, were obtained. Relevant COVID-19–related clinical information, including disease severity, was also collected.

Cases were defined as pregnant women requiring admission for severe or critical COVID-19. Controls were defined as nonpregnant women of reproductive age requiring admission for severe or critical COVID-19. We initially sought to match 3 controls to every 1 case based on age ranges (ie, 18–30, 31–40, and 41–50 years), body mass index (BMI) class (ie, under 30, class I obesity [30–34.9], class II obesity [35–39.9], class III obesity [≥40] kg/m²) and severity of illness (ie, severe [dyspnea, O₂ saturation of ≤ 93%, respiratory rate of ≥30, imaging with >50% lung involvement] vs critical [respiratory failure, shock, and multiorgan dysfunction]). However, as only 96 of the 132 patients were successfully matched, a covariate adjusted analysis was conducted without accounting for matching.

Demographic, pregnancy, and neonatal characteristics were compared between the groups using t tests or Wilcoxon rank sum tests for continuous measures and chi-square or Fisher’s exact tests for the categorical measures as appropriate. The primary outcome was assessed using a logistic regression model of the composite outcomes, adjusted for age, BMI, severity of illness, preexisting cardiac disease (hypertension, coronary artery disease, hyperlipidemia, valvular disease, and congenital heart disease), and preexisting diabetes. The secondary outcomes were evaluated using logistic or linear regression analyses adjusted for age, BMI, severity of illness, preexisting cardiac disease, and preexisting diabetes. Hospital length of stay was log transformed before the analysis. In a subgroup analysis, the primary and secondary outcomes were also assessed only for those patients who met the criteria for severe COVID-19 status on admission using a logistic regression model of the composite outcomes, adjusted for age, BMI, preexisting cardiac disease, and preexisting diabetes. The outcomes were not assessed for those patients meeting the admission criteria for critical COVID-19 status alone because of the small number of patients available for the analysis. Available pregnancy and neonatal outcomes were presented descriptively based on the severity of illness. Presented P values were 2-sided and values of <.05 were considered statistically significant. All analyses were conducted using SAS software version 9.4 (SAS Institute Inc, Cary, NC).

Results

A total of 38 pregnant women with SARS-CoV-2 PCR-confirmed infections were admitted to 5 institutions for severe or critical COVID-19. Of note, 13 pregnant patients (34.2%) were admitted to NYU Langone Health, 10 patients to Mount Sinai Hospital (26.3%), 7 patients to Elmhurst Hospital (18.4%), 5 patients to Montefiore Medical Center (13.2%), and 3 patients to Thomas Jefferson University Hospital (7.9%). Of the 38 pregnant patients admitted for COVID-19, 29 (76.3%) met the criteria for severe disease status and 9 (23.7%) met the criteria for critical disease status. A total of 94 reproductive-aged, nonpregnant women admitted for severe or critical COVID-19 were identified as controls across the institutions. Of note, 22 (23.4%) women admitted to NYU Langone Health, 30 (31.9%) patients to Mount Sinai Hospital, 21 (22.3%) patients to Elmhurst Hospital, 15 (16.0%) patients to Montefiore Medical Center, and 6 (6.4%) patients to Thomas Jefferson University Hospital comprised the control cohort, 80 (85.1%) of these meeting the criteria for severe disease status and 14 (14.9%) meeting the criteria for critical disease status.

The patient demographics are outlined in Table 1 . The mean age (in years) was significantly higher in the nonpregnant controls compared with the pregnant cases (37.9±6.7 vs 34.7±4.3 years; P<.01) (Table 1). The mean BMI on admission was also higher in the nonpregnant controls compared with the pregnant cases (33.4±5.2 vs 31.7±6.6 kg/m²; P=.15) (Table 1). Preexisting diabetes (27.7% vs 10.5%; P=.03) (Table 1) and preexisting cardiac disease (28.7% vs 10.5%, P=.03) (Table 1) were both noted to be significantly higher in the control group.

Pregnant women were more likely to experience the composite morbidity, including death, a need for intubation, ECMO, noninvasive positive pressure ventilation, including BiPAP and CPAP, and a need for high-flow nasal cannula supplementation when compared with the nonpregnant control group (34.2% vs 14.9%; P=.03; adjusted odds ratio [aOR], 4.2; 95% confidence interval [CI], 1.2–18.2) (Table 2 ). A greater percentage of pregnant women received mechanical ventilation compared with the nonpregnant controls (26.3% vs 10.6%; P=.22; aOR, 3.3; 95% CI, 0.5–21.1) (Table 2). However, death and the need for ECMO did not contribute to the primary composite outcome in the pregnant cases. There were no cases of mortality among the pregnant women, whereas death occurred in 3 of the 94 nonpregnant women. In those with severe COVID-19, the pregnant women remained more likely to experience the composite morbidity compared with the nonpregnant control group, although this finding was not statistically significant (13.8% vs 5.0%; P=.09) (Table 3 ). Secondary outcomes are presented in Tables 4 and ​and5.5. The hospital length of stay and ICU length of stay were similar between the groups. However, the rate of ICU admission was higher among the pregnant patients vs the nonpregnant controls (39.5% vs 17.0%; P<.01; aOR, 5.2; 95% CI, 1.5–17.5) (Table 4 ). Pregnant women admitted with severe COVID-19 also had higher rates of ICU admission (20.7% vs 7.5%; P=.03; aOR, 4.9; 95% CI, 1.2–19.5) (Table 5 ) and a longer hospital length of stay (7.3±7.8 vs 5.3± 4.1 days, P=.04; aOR, 0.7; 95% CI, 0.5–1) (Table 5). Although there were no statistically significant differences in other treatment interventions between the groups (Table 6 ), there was a trend toward increased use of antivirals, including lopinavir-ritonavir, oseltamivir, and remdesivir in the pregnant cohort.

The pregnancy and neonatal outcomes are outlined in Table 7 and Table 8 . At the time of analysis, 22 of 38 (58%) patients underwent delivery. The majority of women were delivered through cesarean delivery, regardless of the severity of disease. Worsening maternal status was most often noted to be the indication for delivery in patients with both severe and critical COVID-19 (60.0% and 85.7%, respectively). The mean gestational age at delivery was 33.8±5.5 weeks’ gestation for the severe cases and 35±3.5 weeks’ gestation for the critical cases.

Discussion

Footnotes

References