By Mitchell Linder, MD
Assistant Professor, Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital, Rochester, NY
SYNOPSIS: In this observational cohort study of patients with singleton gestation and positive coronavirus test, patients with severe or critical disease were at risk for perinatal complications compared to those who were asymptomatic. Patients classified with mild or moderate disease were not shown to have an increased risk compared to asymptomatic positive patients.
SOURCE: Metz TD, Clifton RG, Hughes BL, et al. Disease severity and perinatal outcomes of pregnant patients with coronavirus disease 2019 (COVID-19). Obstet Gynecol 2021;137:571-580.
This observational cohort study sought to gather a diverse and representative population of patients throughout the United States to look at perinatal outcomes for singleton gestations infected with SARS-CoV-2 by leveraging the combined research resources of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network of more than 30 academic and community hospitals. Their cohort included all pregnant patients with a singleton gestation and a positive SARS-CoV-2 molecular or antigen test at any of their sites (which are located across 14 states) between March 1, 2020, and July 31, 2020. Eligibility included any patient with a positive test at any point in their pregnancy. Patients with positive antibodies without positive molecular or antigen tests were not included.
Patients meeting eligibility criteria had their data extracted from the electronic medical record by the local research teams and then centralized by an independent data coordinating center. Data extraction included vital signs, imaging results, laboratory values, treatments, complications, intensive care unit (ICU) admissions, and high-intensity interventions, such as intubations, dialysis, and extracorporeal membrane oxygenation for up to 42 days postpartum. Patient self-reported data from the time of SARS-CoV-2 testing also were recorded. Classification of disease severity was according to the National Institutes of Health guidelines for severity of clinical presentation. Maternal outcomes also were tracked, including death, ICU admission, venous thromboembolism, postpartum hemorrhage, hypertensive disorders of pregnancy, and cesarean birth. Neonatal outcomes extracted included perinatal death, positive molecular or antigen SARS-CoV-2 test result during admission, preterm birth prior to 37 weeks gestation, admission to a neonatal intensive care unit (NICU), birth weight, five-minute Apgar score less than 3, and small for gestational age birth weight. Multivariate modeling was used to compare severe-critical and mild-moderate COVID-19 cases to asymptomatic positives.
A total of 1,291 pregnant patients were positive for COVID-19 in the study time frame and 1,219 (94%) had singleton pregnancies and thus were included in the analysis. Five hundred seventy-nine (47%) were asymptomatic, 326 (27%) had mild disease, 173 (14%) had moderate illness, 98 (8%) had severe illness, and 43 (4%) had critical illness. The median gestational age at the time of first positive test was 37.7 weeks gestation. The number of days from first positive test to delivery varied by severity of disease, with a median of four days for severe-critical infections, 18 days for mild-moderate infections, and one day for asymptomatic positives. Overall, 6% of patients had a hospital admission for COVID-19 that was separate from their delivery hospitalization. The most common patient-reported symptoms included cough (34%), dyspnea (19%), and myalgias (19%). Respiratory failure was the most common reason for patients to be classified as having critical illness. Other symptoms common in those with critical status included septic shock (19%), multiple organ dysfunction or failure (61%), tachypnea (67%), decreased O2 saturation values (less than 94%) (63%), and abnormal chest X-ray findings (72%).
Looking at demographic-related findings, severity of illness trends were found to be statistically significantly correlated to age, median body mass index, and insurance status. Race/ethnicity was not found to have a trend in distribution of severity. Medical morbidities showing tests of trend across the severity of illness included asthma or chronic obstructive pulmonary disease (COPD), chronic hypertension, pre-pregnancy diabetes, chronic liver disease, and seizure disorder, meaning those with severe-critical illness and those with mild-moderate illness were more likely to have one of these conditions compared to asymptomatic positives. Overall, 12% of patients had severe or critical illness. In terms of maternal and neonatal outcomes, tests of trend across disease severity were statistically significant for maternal death, venous thromboembolism, maternal ICU admission, cesarean birth, hypertensive disorders of pregnancy, preterm birth less than 37 weeks gestation, low birth weight, and NICU admission, again showing adverse maternal and fetal outcomes were worse in those with severe illness.
Iatrogenic preterm births occurred in 83% of patients with severe-critical disease compared to 61% in those with mild-moderate disease and 49% of the asymptomatic positives (P < 0.001 for trend across severity). Of the 67 preterm inductions, COVID-19 was the primary indication for delivery in only 3% of cases. The most common indications for induction were hypertensive disorders (33%), stillbirth (16%), and preterm prelabor rupture of membranes (33%). Twenty-two percent (n = 106) of those who had a preterm cesarean delivery had COVID-19 as their diagnosis. Other common indications for preterm birth by cesarean delivery included non-reassuring fetal status (29%), hypertensive disorders of pregnancy (15%), and abnormal presentation (11%).
One percent (95% confidence interval, 0.5% to 1.8%) of neonates tested positive for SARS-CoV-2 prior to discharge. Among patients who were offered maternal-neonatal separation (n = 448, 37%), 312 actually were separated (26%), which broke down to 59 out of 64 (92%) with severe-critical illness, 77 out of 126 (61%) with mild-moderate illness, and 176 out of 258 (68%) who were asymptomatic positives.
Although we now are more than a year into the global pandemic, our knowledge of how this illness affects pregnancy, as well as maternal and/or neonatal outcomes, continues to be somewhat elusive because of deficiencies in reporting structures and lack of collective, representative healthcare data derived from the decentralized structure of the United States healthcare system. Most studies to date have been single-site entries or systematic reviews or meta-analyses with all of their inherent flaws.
The authors pointed out that their study helps to clarify the existing data regarding pregnancy and COVID-19 infection by being able to determine the reasons behind admission as opposed to what generally is collected by the Centers for Disease Control and Prevention (simple admission and positive [but could be because of labor] vs. admission specifically for COVID-19 infection). They also noted that they found higher rates of maternal death (0.3%, 3/1,000 patients) and ICU admission (4.8%, 48/1,000 patients) than have been published previously. The authors speculated this could be related to the increased influx of sicker patients via interhospital transfers, although overall that accounted only for 11% of the severe-critical patients. Therefore, they concluded that it more likely is related to the depth of record extraction that was available, allowing a better clinical picture to emerge.
The biggest strength of this study is derived from the fact that their data come from a widespread geographic set of locations representing a demographically and socioeconomically diverse group of patients. This large cross-section of the population helps make their results more generalizable for any given setting. Limitations noted by the authors include the fact that the mean gestational age at the time of infection was late in the third trimester, largely caused by the timing of the study and the fact that the first wave of COVID-19 infections in the United States did not begin until at least March 2020. This is important to note since it limited their ability to look at outcomes, such as congenital anomalies and miscarriage. In addition, given that treatment regimens over this observational time course were not standardized and were evolving continuously, they were unable to evaluate the effects on outcomes of any treatments used during the study window.
As we continue to watch waves of COVID-19 ebb and flow across the country, it is important to remember that, although pregnant patients may not have increased susceptibility to infection, they do seem to have worse clinical courses compared to nonpregnant patients.1 This is true especially in patients with certain medical co-morbidities and demographic factors. There is an ever-growing body of evidence regarding the safety of messenger RNA COVID-19 vaccine use in pregnancy and the fact that COVID-19 vaccines have been shown to reduce the risk of moderate to severe disease by 72% to 95% (depending on vaccine given). This study provides another set of data points that suggest we as clinicians should continue to do everything in our power to help address vaccine hesitancy in those who are pregnant and/or planning to become pregnant, especially among our minority patients (given they are independently at higher risk for severe adverse maternal and neonatal outcomes).2-4
- Zambrano LD, Ellington S, Strid P, et al. Update: Characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status — United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1641-1647.
- Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N Engl J Med 2021; Apr 21. doi: 10.1056/NEJMoa2104983. [Online ahead of print].
- Advisory Committee on Immunization Practices. COVID-19 ACIP vaccine recommendations. Centers for Disease Control and Prevention. Last reviewed May 17, 2021. https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html
- Howell EA. Reducing disparities in severe maternal morbidity and mortality. Clin Obstet Gynecol 2018;61:387-399.