Abstract
BACKGROUND: Despite previous research findings on higher risks of stillbirth among pregnant individuals with SARS-CoV-2 infection, it is unclear whether the gestational timing of viral infection modulates this risk. OBJECTIVE: This study aimed to examine the association between timing of SARS-CoV-2 infection during pregnancy and risk of stillbirth. STUDY DESIGN: This retrospective cohort study used multilevel logistic regression analyses of nationwide electronic health records in the United States. Data were from 75 healthcare systems and institutes across 50 states. A total of 191,403 pregnancies of 190,738 individuals of reproductive age (15-49 years) who had childbirth between March 1, 2020 and May 31, 2021 were identified and included. The main outcome was stillbirth at ≥20 weeks of gestation. Exposures were the timing of SARS-CoV-2 infection: early pregnancy (<20 weeks), midpregnancy (21-27 weeks), the third trimester (28-43 weeks), any time before delivery, and never infected (reference). RESULTS: We identified 2342 (1.3%) pregnancies with COVID-19 in early pregnancy, 2075 (1.2%) in midpregnancy, and 12,697 (6.9%) in the third trimester. After adjusting for maternal and clinical characteristics, increased odds of stillbirth were observed among pregnant individuals with SARS-CoV-2 infection only in early pregnancy (odds ratio, 1.75, 95% confidence interval, 1.25-2.46) and midpregnancy (odds ratio, 2.09; 95% confidence interval, 1.49-2.93), as opposed to pregnant individuals who were never infected. Older age, Black race, hypertension, acute respiratory distress syndrome or acute respiratory failure, and placental abruption were found to be consistently associated with stillbirth across different trimesters. CONCLUSION: Increased risk of stillbirth was associated with COVID-19 only when pregnant individuals were infected during early and midpregnancy, and not at any time before the delivery or during the third trimester, suggesting the potential vulnerability of the fetus to SARS-CoV-2 infection in early pregnancy. Our findings underscore the importance of proactive COVID-19 prevention and timely medical intervention for individuals infected with SARS-CoV-2 during early and midpregnancy.