High rates of severe maternal morbidity and preterm birth among pregnant individuals with sickle cell disease, a nationwide study from 2020-2024

Abstract Introduction: Previous data demonstrate that pregnant individuals with sickle cell disease (SCD) face significantly elevated risks of severe maternal morbidity (SMM). Black individuals without SCD are also at high risk for SMM. A study of the National Inpatient Sample (NIS) from 2012-2018 showed that compared with non-Black patients, the adjusted odds of SMM were 7.22 (95% CI: 6.25-8.34) times higher in individuals with SCD and 1.45 (95% CI: 1.41-1.50) times higher in Black individuals without SCD, indicating that SCD confers a substantially greater risk beyond that associated with race alone (Early et al., 2023). However, these estimates were limited by older data and the lack of key clinical variables in the NIS, which may hinder adequate adjustment for confounding. To address these limitations and expand our understanding of delivery outcomes, we leveraged Epic Cosmos, a contemporary nationwide electronic health record (EHR) database, to provide updated estimates of both SMM and preterm birth (PTB) among individuals with SCD. Methods: We conducted a retrospective cohort study using Cosmos, which includes clinical data from >300 million patients across all U.S. states and spans 1,748 hospitals. We identified all delivery encounters from 2020-2024, and to ensure patients contributed data only once, we randomly selected one delivery per patient with >1 pregnancy during the study period. SCD cases were defined as individuals with ≥3 encounters containing SMM was defined using the CDC algorithm that includes codes for 16 conditions and 5 procedures. To better isolate SMM events unrelated to the baseline SCD disease burden, we also conducted an analysis excluding sickle cell crisis and transfusion from the CDC definition of SMM. We performed multivariable logistic regression to estimate adjusted odds ratios (aORs), and controlled for covariates including year of delivery, gestational age at birth, pregnancy-related conditions, and socioeconomic status. We compared the risk of SMM to all controls without SCD as well as to Black controls without SCD. We next evaluated PTB, defined as gestational age <37 weeks, by comparing rates between patients with SCD and healthy controls, with and without restriction to Black patients. Results: We identified 2,679 deliveries among pregnant individuals with SCD and 2,818,826 deliveries among those without SCD. Among Black or African American patients, 0.5% had SCD, consistent with national prevalence estimates. The incidence of SMM during the delivery encounter was 25% in those with SCD, compared to 2.4% in those without (aOR 8.67, 95% CI 7.76-9.67; p<0.001). When SMM was redefined to exclude sickle cell crisis and transfusion, the adjusted odds of SMM for patients with SCD remained significantly elevated (aOR 4.61, 95% CI 4.06-5.23; p<0.001). After restriction to Black or African American individuals, the adjusted odds ratio for all SMM among patients with SCD compared to controls was 8.97 (95% CI: 7.98-10.07; p<0.001) and for SMM exclusive of sickle cell crisis or transfusion was 3.47 (95% 2.87, 4.18; p<0.001). The adjusted odds of PTB were 1.66 times higher for individuals with SCD compared to those without (95% CI 1.48-1.86; p<0.001). When restricted to Black or African American patients, people with SCD remained at significantly increased risk of PTB (aOR 1.72, 95% CI 1.52-1.93; p<0.001). Conclusions: In the first nationwide study to use a large-scale, contemporary EHR database to evaluate SMM and delivery outcomes among pregnant individuals with SCD, we found that those with SCD have a significantly elevated risk of SMM. This risk persisted after multivariable adjustment, removal of sickle cell crisis and transfusions, and restricting to Black patients. In addition, we identified a significantly higher risk of PTB in patients with SCD, demonstrating another dimension of adverse pregnancy outcomes in this population. To our knowledge, this is the most comprehensive and current EHR-based analysis of maternal outcomes in SCD, including data from the post-COVID-19 era. Future directions include leveraging Cosmos to examine additional fetal and maternal outcomes, evaluate transfusion burden, and explore associations with baseline lab features. Our results reinforce the ongoing urgency to improve maternal outcomes in this high-risk population.