Study design and study population
During the first-wave peak of COVID-19 infections in the US, testing for COVID-19 became universal for all pregnancy admissions from April 2020 in Illinois, USA. We conducted a retrospective cohort study between April 1 and August 15, 2020 that included all consecutive pregnant women who were admitted at any gestational age and had laboratory-confirmed COVID-19. Admissions were from two Chicago maternity hospitals— John H. Stroger, Jr. Hospital of Cook County and AMITA St. Mary’s and Elizabeth Hospital. Our study was possible because of the April 2020 implementation of universal COVID-19 testing for all pregnant women admitted to hospitals in Illinois. We followed the World Health Organization (WHO) guidelines for diagnosis, which define positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal or pharyngeal swabs as laboratory-confirmed SARS-CoV-2.17 Patients with lack of data on symptoms and an inconsiderable number of other clinical characteristics, including risk factors and maternal and perinatal outcomes, were excluded. We further included their newborns in the study, who were also tested for SARS-CoV-2 infection using throat swabs.
Ethical approval and data collection
The study's protocol was expeditiously approved by the institutional research ethics committees associated with John H. Stroger, Jr. Hospital of Cook County (approval number: 20–098) and AMITA Health Saints Mary and Elizabeth Medical Center (approval number: 2021-0193-02). The requirement of informed consent was waived due to the retrospective study design.
The following demographic and baseline maternal data were collected: age, race and ethnicity, anthropometric characteristics (e.g., BMI), lifestyle habits including substance abuse, comorbidities including pregestational obesity, hypertension, and gestational diabetes; whether the patient received antepartum therapy including hydroxychloroquine treatment. All participants underwent clinical evaluation of presenting signs and symptoms, detailed laboratory assessment of blood and urine samples, and radiologic chest assessment, if needed.
Maternal blood sample assessment included hemoglobin, blood cell counts, inflammatory markers (e.g., C-reactive protein [CRP]), serum concentration of electrolytes (sodium, potassium, calcium, and chloride), liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), and renal function (blood urea nitrogen [BUN] and creatinine). Data on pregnancy outcomes (including mode of delivery, gestational age (GA), and preeclampsia), and neonatal outcomes (including symptoms, APGAR scores, and birth weight) were recorded. A preterm birth or premature birth was defined as one occurring at < 37 weeks. We used specific cut-off values to define blood dyscrasias for pregnant women according to their trimester: leukopenia as white cell count < 5.9 x 109/L, neutropenia as neutrophil count < 3.9 x 109/L, and lymphopenia as lymphocyte count < 1.0 x 109/L 18 for the third trimester.
We also performed the gross and histopathological evaluation of placentas according to the Amsterdam consensus statement guidelines.19
We assessed the effect of length of duration of fetal exposure to maternal SARS-CoV-2 and the possibility of increased risk of vertical transmission, morbidity, and mortality specifically among preterm infants (< 37 weeks of gestation). We sub-analyzed women who were infected prior to 37 weeks of gestation, focusing on evidence of SARS-CoV-2 infection among preterm infants born to these women, including positive RT-PCR testing and any clinical signs/symptoms attributable to infection.
We further performed laboratory assessment of blood samples taken from the newborns and followed up both mother and infant until six weeks after delivery. We defined the infant's specific blood dyscrasias according to their age of life: leukopenia as white cell count < 13.0 x 109/L for term infants at 1–12 hours of life and < 9.0 x 109/L for preterm infants at birth; neutropenia as neutrophil count < 6.0 x 109/L for term infants at 1–12 hours of life and < 6.0 x 109/L for preterm infants at birth; and lymphopenia as lymphocyte count < 2.0 x 109/L for both term infants at 1–12 hours of life and preterm infants at birth.21 Evidence of vertical transmission was further evaluated for the presence of SARS-CoV-2 according to CDC guidelines.22 As, and when, appropriate we evaluated infants for immunoglobulin [Ig] G and IgM levels.
All the data collected was curated using a customized data collection form, and two study investigators (JM and BP) independently reviewed the data collection forms for any errors. The data was locked and secured appropriately according to rules and principles laid down in the Health Insurance Portability and Accountability Act of 1996 (HIPAA). The data collected from both sites was synchronized and any inaccuracies were verified with the concerned representative of the specific center.
The patients were further classified into two groups: symptomatic and asymptomatic, according to the existence of any of known signs and symptoms of COVID-19 infection.
Statistical analyses were conducted using STATA/IC 16 (Stata-Corp LP, TX, SA) and SAS 9.4 (SAS Institute, Inc., Cary, NC). Continuous variables were expressed as mean and standard deviation (SD) for normally distributed data, median and range for non-normally distributed data, and categorical variables as frequency and percentage. The continuous variables were compared between symptomatic and asymptomatic individuals using a t-test or Mann-Whitney-U test and categorical variables were compared using the Pearson chi-square test or Fisher's-exact test, as appropriate. We calculated the unadjusted odds ratio (OR) using the simple logistic regression model. A p-value of < 0.05 was considered statistically significant.