While pregnancy has been associated with an altered immune response and distinct clinical manifestations of COVID-19, the influence of pregnancy on the persistence and severity of post-acute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, remains uncertain. This study investigated PASC risk in individuals with SARS-CoV-2 infection during pregnancy and compared it with that in reproductive-age females with SARS-CoV-2 infection outside of pregnancy. This retrospective analysis identified 72,151 individuals who contracted SARS-CoV-2 during pregnancy and 1,439,354 females who contracted SARS-CoV-2 outside of pregnancy, aged 18 to 50 years old, from March 2020 to June 2023 in the National Patient-Centered Clinical Research Network (PCORnet) and the National COVID Cohort Collaborative (N3C). A comprehensive list of PASC outcomes was investigated, including a PCORnet rule-based PASC definition, an N3C PASC machine learning (ML) Phenotype, unspecified PASC ICD-10 diagnoses (ICD10 codes U09.9 or B94.8), and a cluster of cognitive, fatigue, and respiratory conditions. Overall, the estimated risk of PASC at 180 days of follow-up for those infected during pregnancy was 16.47 events per 100 persons (95% CI, 16.00 to 16.95) in the PCORnet cohort, based on the PCORnet rule-based PASC definition, and 4.37 events per 100 persons (95% CI, 4.18 to 4.57) in the N3C cohort based on the ML model. The risks of unspecified PASC diagnoses were 0.19 events per 100 persons (95% CI, 0.14 to 0.25) in PCORnet, and 0.23 events per 100 persons (95% CI, 0.19 to 0.28) in N3C; and the risks of any post-acute cognitive, fatigue, and respiratory condition were 4.86 events per 100 persons (95% CI, 4.59 to 5.14) in PCORnet, and 6.83 events per 100 persons (95% CI, 6.59 to 7.08) in N3C. The PASC risk varied across different subpopulations within pregnant females. The observed risk factors for PASC included self-reported Black race, advanced maternal age, infection during the first two trimesters, obesity, and the presence of baseline comorbid conditions. While the findings suggest a high incidence of PASC in individuals following SARS-CoV-2 infection during pregnancy, the risk of PASC in pregnant females was lower than in matched non-pregnant females.
